Therapeutic heterocycles

ABSTRACT

Compounds of formula I                    
     wherein G, J, L, M, m and D have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of neurokinin A and useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.

This is a divisional of application Ser. No. 09/336,087 filed Jun. 18,1999, now U.S. Pat. No. 6,124,279, which is a divisional of applicationSer. No. 09/106,606 filed Jun. 28, 1998, now U.S. Pat. No. 5,990,130,which is a divisional of application Ser. No. 081689,199 filed Aug. 8,1996, now U.S. Pat. No. 5,861,392, which is a divisional of parentapplication Ser. No. 08/290,642 filed Aug. 15, 1994, now U.S. Pat. No.5,567,700.

This invention concerns novel therapeutic heterocycles, and, moreparticularly, novel 4-substituted piperidine derivatives whichantagonize the pharmacological actions of one of the endogenousneuropeptide tachykinins known as neurokinins, particularly at theneurokinin 2 (NK2) receptor. The novel therapeutic heterocycles areuseful whenever such antagonism is desired. Thus, such compounds may beof value in the treatment of those diseases in which an NK2 receptor isimplicated, for example, in the treatment of asthma and relatedconditions. The invention also provides pharmaceutical compositionscontaining the novel therapeutic heterocycles for use in such treatment,methods for their use, and processes and intermediates for themanufacture of the novel therapeutic heterocycles.

The mammalian neurokinins comprise a class of peptide neurotransmitterswhich are found in the peripheral and central nervous systems. The threeprincipal neurokinins are Substance P (SP), Neurokinin A (NKA) andNeurokinin B (NKB). There are also N-terminally extended forms of atleast NKA. At least three receptor types are known for the threeprincipal neurokinins. Based upon their relative selectivities favoringthe neurokinin agonists SP, NKA and NKB, respectively, the receptors areclassifed as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3(NK3) receptors, respectively. In the periphery, SP and NKA arelocalized in C-afferent sensory neurons, which neurons are characterizedby non-myelinated nerve endings known as C-fibers, and are released byselective depolarization of these neurons, or selective stimulation ofthe C-fibers. C-Fibers are located in the airway epithelium, and thetachykinins are known to cause profound effects which clearly parallelmany of the symptoms observed in asthmatics. The effects of release orintroduction of tachykinins in mammalian airways includebronchoconstriction, increased microvascular permeability, vasodilationand activation of mast cells. Thus, the tachykinins are implicated inthe pathophysiology and the airway hyperresponsiveness observed inasthmatics; and blockade of the action of released tachykinins may beuseful in the treatment of asthma and related conditions.

Peptidic NK2 antagonists have been reported. For example, a cyclichexapeptide known as L-659,877 has been reported as a selective NK2antagonist. Nonpeptidic NK2 antagonists also have been reported, forexample, certain piperidines are disclosed in European PatentApplications, Publication Numbers 428434, 474561, 512901, 512902,515240, and 559538. A series of piperidine NK2 antagonists has also beenreported in International Application, Publication Number WO 94/10146.

We have discovered a series of novel nonpeptidic NK2 antagonists andthis is the basis for our invention. One aspect of the discoveryincludes 4-substituted piperidino derivatives in which the 4-substituentis an N-linked heterocycle (as defined below). For example, wediscovered the 4-(2-oxo-1,3-oxazolidin-3-yl)piperidino compounddisclosed below at Example 1 to be a potent NK2 antagonist in the invitro screen described below as Test A and in the functional assaydescribed below as Test B.

According to the invention, there is provided a Compound of theinvention; which is a compound of formula I (formula set out hereinbelowfollowing the Examples, together with other formulae denoted by Romannumerals) wherein

m is 2 or 3;

D is a residue of formula Ia or formula Ib wherein

Q is phenyl which may bear one or two substituents independentlyselected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyland methylenedioxy; or Q is thienyl, imidazolyl, benzo[b]thiophenyl ornaphthyl any of which may bear a halo substituent; or Q is biphenylyl;or Q is carbon-linked indolyl which may bear a benzyl substituent at the1-position;

Q^(a) is hydrogen, (1-4C)alkyl, or a radical of formula —(CH₂)_(q)—NR⁵R⁶in which q is 2 or 3 and R⁵ and R⁶ are independently (1-4C)alkyl orNR⁵R⁶ is piperidino or 4-benzylpiperidino;

R¹ is hydrogen, methyl or (2-6C)n-alkyl which may bear a terminal aminoradical;

R² is —C(═O)R³, —C(=O)OR³ or —C(═J¹)NHR³ in which J¹ is oxygen or sulfurand R³ is hydrogen, (1-6C)alkyl, phenyl(1-3C)alkyl (in which the phenylmay bear one or more halo, hydroxy, (1-4C)alkoxy or (1-4C)alkylsubstituents), pyridyl(1-3C)alkyl, naphthyl(1-3C)alkyl,pyridylthio(1-3C)alkyl, styryl, 1-methylimidazol-2-ylthio(1-3C)alkyl,aryl (which may bear one or more halo, hydroxy, (1-4C)alkoxy or(1-4C)alkyl substituents), heteroaryl (which may bear one or more halo,hydroxy, (1-4C)alkoxy or (1-4C)alkyl substituents), or (when R² is—COR³) α-hydroxybenzyl;

n is 0, 1, 2 or 3;

p is 1 or 2, and when p is 2, n is 1 and J² is two hydrogens;

J² is oxygen or two hydrogens;

L is carbonyl or methylene;

r is 0, 1, 2, or 3; and

R⁴ is phenyl which may bear one or more halo, trifluoromethyl,(1-4C)alkyl, hydroxy or (1-4C)alkoxy substituents (and particularly oneor more chloro or fluoro substituents); naphthyl which may bear one ormore halo, trifluoromethyl, (1-4C)alkyl or hydroxy substituents;pyridyl; thienyl; indolyl; quinolinyl; benzothienyl or imidazolyl; orwhen L⁶ is carbonyl, the group —(CH₂)_(r)—R⁴ may represent aryl,heteroaryl or a benzyl group bearing an α-substituent selected fromhydroxy, (1-4C)alkoxy and (1-4)alkyl, and further wherein the aryl,heteroaryl or phenyl portion of the benzyl group may bear one or moresubstituents selected independently from halo, trifluoromethyl,(1-4C)alkyl, hydroxy and (1-4C)alkyl, hydroxy and (1-4C)alkoxy (andparticularly one or more chloro or,fluoro substituents);

G denotes a single bond, a double bond or a divalent hydrocarbonradical;

J denotes a radical joined to the ring by a single bond if G denotes adouble bond or, otherwise, a radical joined by a double bond;

M denotes a heteroatom or substituted heteroatom; and

L denotes a hydrocarbon radical in which the 1-position is attached toM; wherein

the values of G, J, M and L are selected from

(a) G is a single bond; J is oxo or thioxo; M is oxy, thio or NR¹²; andL is L¹;

(b) C is a single bond; J is NR⁸; M is NR⁷; and L is L¹;

(c) G is a double bond, J is OR⁷, SR⁷ or NR⁹R¹⁰; M is nitrogen; and L isL¹;

(d) G is methylene which may bear one or two methyl substituents; J isoxo, thio or NR¹¹; M is oxy, thio, sulfinyl, sulfonyl or NR⁷; and L isL²;

(e) G is a single bond; J is oxo, thioxo or NR¹¹; M is nitrogen; and Lis L³;

(f) G is methine, which may bear a (1-3C)alkyl substituent; J is oxo,thioxo or NR¹¹; M is nitrogen; and L is L⁴; and

(g) G is cis-vinylene, which may bear one or two methyl substituents; Jis oxo, thioxo, or NR¹¹; M is nitrogen; and L is L⁵; wherein

R is hydrogen or (1-3C)alkyl;

R⁸ is hydrogen, (1-3C)alkyl, cyano, (1-3C)alkylsulfonyl or nitro;

R⁹ and R¹⁰ are independently hydrogen or (1-3C)alkyl or the radicalNR⁹R¹⁰ is pyrrolidino, piperidino, morpholino, thiomorpholino (or itsS-oxide) or piperazino (which may bear a (1-3C)alkyl substituent at the4-position);

R¹¹ is hydrogen or (1-3C)alkyl;

R¹² is hydrogen, (1-3C)alkyl, RaOC(═O)CH₂— or RbRcNC(═O)CH₂—.

R^(a) is hydrogen or (1-3C)alkyl;

R^(b) and Rc are independently hydrogen, (1-3C)alkyl, phenyl or benzyl;

L¹ is ethylene, cis-vinylene, trimethylene or tetramethylene whichradical L¹ itself may bear one or two methyl substituents;

L² is ethylene or trimethylene which radical L² itself may bear one ortwo methyl substituents;

L³ is prop-2-en-1-yliden-3-yl, which radical L³ itself may bear one ortwo methyl substituents;

L⁴ is cis-vinylene, which radical L⁴ itself may bear one or two methylsubstituents; and

L⁵ is methine, which radical L⁵ itself may bear a (1-3C)alkylsubstituent;

or the N-oxide of said compound of formula I at the piperidino nitrogenindicated by Δ;

or a pharmaceutically acceptable salt of said compound of formula I orsaid N-oxide;

or a quaternary ammonium salt of said compound of formula I in which thepiperidino nitrogen indicated by Δ is a quadricovalent ammonium nitrogenwherein the fourth radical on the nitrogen is (1-4C)alkyl or benzyl andthe associated counterion is a pharmaceutically acceptable anion.

It will be appreciated that a compound of formula I contains one or moreasymmetrically substituted carbon atoms such that such a compound may beisolated in optically active, racemic and/or diastereomeric forms. Itwill further be appreciated that a compound of formula I may exist intautomeric forms and that a compound may exhibit polymorphism. It is tobe understood that the present invention encompasses any racemic,optically-active, diastereomeric, tautomeric, polymorphic orstereoisomeric form, or mixture thereof, which form possesses NK2antagonist properties, it being well known in the art how to prepareoptically-active forms (for example, by resolution of the racemic formor by synthesis from optically-active starting materials) and how todetermine the NK2 antagonist properties by the standard tests describedhereinafter. It may be preferred to use the compound of formula I in aform which is characterized as containing, for example, at least 95%,98% or 99% enantiomeric excess. Further, it may be preferred to use acompound of formula I, which is a compound of formula Ic, in a formwhich is characterized as containing, for example, at least 95%, 98% or99% enantiomeric excess of the form with the (S)-configuration at thecenter indicated by * in the formula.

In this specification R^(a), R^(b), R¹, R², et cetera stand for genericradicals and have no other significance. It is to be understood that thegeneric term “(1-3C)alkyl” includes both straight and branched chainalkyl radicals but references to individual alkyl radicals such as“propyl” embrace only the straight chain (“normal”) radical, branchedchain isomers such as “isopropyl” being referred to specifically. Asimilar convention applies to other generic groups, for example, alkoxy,alkanoyl, et cetera. Halo is fluoro, chloro, bromo or iodo.

Particular values are listed below for radicals, substituents and rangesfor Compounds for illustration only and they do not exclude otherdefined values or other values within defined ranges for the radicalsand substituents.

A particular value for m is 2.

A particular value for (1-6C)alkyl is methyl, ethyl, propyl, isopropylor butyl.

A particular value for (1-3C)alkyl is methyl or ethyl.

When D is formula Ia, a particular value for Q^(a) is hydrogen, aparticular value for R¹ is methyl and a particular value for R² is—COR³. A particular value for R³ is aryl, and more particularly phenyl,which aryl (or phenyl) may bear one or two chloro or fluorosubstituents.

When D is formula Ib, a particular value for n is 1 or 2; a particularvalue for p is 1; a particular value for J² is two hydrogens; aparticular value for L⁶ is carbonyl; a particular value for r is 0 or 1;and a particular value for R⁴ is phenyl which may bear one or two haloor (1-4C)alkoxy substituents, and more particularly a chloro, fluoro orisopropoxy substituent.

A particular value for Q is, for example, phenyl which may bear one ortwo substituents selected from halo, trifluoromethyl and methylenedioxy;and, more particularly, 3,4-dichlorophenyl or 3,4-methylenedioxyphenyl.

A particular value for G is, for example, a single bond or methylene;and, more particularly, a single bond. A particular value for J is, forexample, oxo, thioxo, imino, methylimino or ethylimino; and, moreparticularly, oxo or thioxo. A particular value for M is oxy, thio orNH; and, more particularly, oxy or NH. A particular value for L is, forexample ethylene, cis-vinylene or trimethylene; and, more particularly,ethylene or trimethylene.

A particular group of compounds of formula I are compounds of formula Icwherein: Q^(b) is phenyl which may bear one or two substituentsindependently selected from halo, trifluoromethyl, hydroxy,(1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q^(b) is thienyl,imidazolyl, benzo[b]thiophenyl or naphthyl any of which may bear a halosubstituent; or Q^(b) is biphenylyl; or Q^(b) is carbon-linked indolylwhich may bear a benzyl substituent at the 1-position; T and U areindependently hydrogen, halo, hydroxy, (1-3C)alkyl or (1-3C)alkoxy; W is(1-3C) alkyl; and G, J, L and M have any of the meanings defined for thecorresponding radical in a compound of formula I; or the N-oxide of saidcompound of formula I at the piperidino nitrogen indicated by Δ; or apharmaceutically acceptable salt of said compound of formula I or saidN-oxide; or a quaternary ammonium salt of said compound of formula I inwhich the piperidino nitrogen indicated by Δ is a quadricovalentammonium nitrogen wherein the fourth radical on the nitrogen is(1-4C)alkyl or benzyl and the associated counterion is apharmaceutically acceptable anion.

Another particular group of compounds of formula I are compounds offormula Ic wherein: R¹² is hydrogen or (1-3C)alkyl; T and U arehydrogen; and W is methyl; and pharmaceutically acceptable saltsthereof.

Preferred compounds include(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide;(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide;(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)-piperidino]butyl]-N-methylbenzamide;and(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)-piperidino]butyl]-N-ethylbenzamide;and pharmaceutically acceptable salts thereof.

Specific Compounds are described in the accompanying Examples.

A pharmaceutically acceptable salt is one made with an acid whichprovides a physiologically acceptable anion. Pharmaceutically acceptablesalts include those made with a strong inorganic or organic acid whichaffords a physiologically acceptable anion, such as, for example,hydrochloric, sulfuric, phosphoric, methanesulfonic, orp-toluenesulfonic acid.

A Compound may be made by processes which include processes known in thechemical art for the production of structurally analogous heterocycliccompounds. Such processes and intermediates for the manufacture of acompound of formula I; or the N-oxide of said compound of formula I atthe piperidino nitrogen indicated by Δ; or a pharmaceutically acceptablesalt of said compound of formula I or said N-oxide; or a quaternaryammonium salt of said compound of formula I in which the piperidinonitrogen indicated by Δ is a quadricovalent ammonium nitrogen whereinthe fourth radical on the nitrogen is (1-4C)alkyl or benzyl and theassociated counterion is a pharmaceutically acceptable anion; as definedabove, are provided as further features of the invention and areillustrated by the following procedures in which the meanings of genericradicals are as defined above unless otherwise indicated:

(a) Alkylating a piperidine of formula II with an aldehyde of formulaIV, by reductive alkylation, or with an alkylating agent of formula V inwhich Y is a leaving group. Typical values for a leaving group Yinclude, for example, iodide, bromide, methanesulfonate,p-toluenesulfonate, trifluoromethanesulfonate, and the like. Thealkylation is preferably carried out by a conventional reductivealkylation, for example as described in Example 1, by the in situ,acid-catalyzed formation of an imminium salt, followed by reduction withsodium cyanoborohydride in alcoholic solvent.

(b) For a compound of formula I in which G is a single bond; J is oxo orthioxo, respectively; M is oxy, thio or NR¹²; and L is L¹; cyclizing acorresponding compound of formula III with a diactivated derivative ofcarbonic acid or a diactivated thiocarbonyl derivative, respectively.Diactivated derivatives of carbonic acid include, for example,1,1′-carbonyldiimidazole, chloroformate esters (such as the methyl,ethyl or phenyl ester) and carbonate diesters, as well as phosgene,diphosgene and triphosgene; and diactivated thiocarbonyl derivativesinclude, for example, 1,1′-thiocarbonyldi-2(1H)-pyridone,1,1′-thiocarbonyldiimidazole, phenyl chlorodithioformate andthiophosgene. Conveniently, the cyclization is carried in an inertsolvent, for example chloroform, tetrahydrofuran or toluene, at atemperature from about ambient temperature to the reflux temperature ofthe reaction mixture, for example as described in Example 3. If thediactivated derivative of carbonic acid or the diactivated thiocarbonylderivative is an acid chloride, it may be preferred to add a base, suchas for example triethylamine, to the cyclization as an acid acceptor.

(c) For a compound of formula I which is a compound of formula Ic;reacting an amine of formula VIII with a suitable acid chloride. Thereaction may be carried out in an inert solvent, such as for example,tetrahydrofuran, diethyl ether, toluene, chloroform or dichloromethane,at a temperature in the range of −78 to 100° C., preferably in the rangeof −20 to 50° C. The reaction may be carried out, for example, underconditions similar to those described in Example 17.

(d) For a compound of formula I which is a compound of formula Ic;reacting an amine of formula VIII with an activated carboxylic acidderivative. The reaction may be carried out in an inert solvent, such asfor example, tetrahydrofuran, diethyl ether, toluene, chloroform ordichloromethane, at a temperature in the range of −78 to 100° C.,preferably in the range of °20 to 50° C., in the presence of a suitableactivating agent, for example,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Thereaction may be carried out, for example, under conditions similar tothose described in Example 20.

(e) For an N-oxide of a compound of formula I at the piperidino nitrogenindicated by A, oxidizing the piperidino nitrogen indicated by α of acompound of formula I using a conventional procedure, such as, forexample, using hydrogen peroxide in methanol, peracetic acid,3-chloroperoxybenzoic acid in an inert solvent (such as dichloromethane)or dioxirane in acetone. Suitable conditions, for example, are describedin Example 21.

(f) For a compound of formula I wherein R¹² is (1-3C)alkyl, RaOC(═O)CH₂—or RbRcNC(═O)CH₂—, alkylating a corresponding compound of formula Iwherein R¹² is hydrogen with a suitable corresponding alkylating agent.The alkylation may be carried out in an inert solvent, such as forexample, tetrahydrofuran, diethyl ether, toluene or 1,2-dimethoxyethane,at a temperature in the range of −78 to 100° C., preferably in the rangeof 0-50° C., in the presence of a suitable base. Suitable conditions,for example, are described in Example 22.

(g) For a quaternary ammonium salt of a compound of formula I,alkylating the piperidino nitrogen indicated by α of the compound offormula I with a suitable alkylating agent. The alkylation may becarried out in an inert solvent, such as for example, tetrahydrofuran,diethyl ether, toluene or 1,2-dimethoxyethane, at a temperature in therange of −78 to 100° C., preferably in the range of 0-50° C., in thepresence of a suitable base.

It may be desired to optionally use a protecting group during all orportions of the above described processes; the protecting group then maybe removed when the final compound is to be formed.

Whereafter, for any of the above procedures, when a pharmaceuticallyacceptable salt of a compound of formula I or a pharmaceuticallyacceptable salt of an N-oxide of a compound of formula I is required, itmay be obtained by reacting the corresponding compound of formula I orN-oxide with an acid affording a physiologically acceptable counterionor by any other conventional procedure.

It will also be appreciated that certain of the various optionalsubstituents in the Compounds may be introduced by standard aromaticsubstitution reactions or generated by conventional functional groupmodifications either prior to or immediately following the processesabove, and as such are included in the process aspect of the invention.Such reactions and modifications include, for example, introduction ofnitro or halogeno and reduction of nitro. The reagents and reactionconditions for such procedures are well known in the chemical art.

If not commercially available, the necessary starting materials for theabove procedures may be made by procedures which are selected fromstandard techniques of heterocyclic chemistry, techniques which areanalogous to the synthesis of known, structurally similar compounds, andtechniques which are analogous to the above described procedures or theprocedures described in the Examples. The starting materials and theprocedures for their preparation are additional aspects of theinvention.

A convenient intermediate for preparation of starting materials offormulae III, IV, and V is an alcohol of formula VI (or VIc). Thepreparation of an alcohol of formula VIc in which Q^(b) is3,4-dichlorophenyl is described in Example 1, parts a)-f); and thepreparation of the corresponding optically-active alcohol is describedin Example 2, parts a)-e). An alcohol of formula VI may then be oxidizedto an aldehyde of formula IV, for example using oxalyl chloride,dimethyl sulfoxide and triethylamine as described in Example 1.g) orusing Dess-Martin periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) as described inExample 2.f); or it may be converted into an alkylating agent of formulaV by a conventional procedure. An aldehyde of formula IV may beconverted into the corresponding amine of formula III employing aprocedure similar to that described in Example 3, parts a)-e). Using aprocedure similar to that described in Example 1, an aldehyde of formulaIV may be converted into a piperidone of formula VII; and an amine offormula III may be obtained by reductive alkylation of an amine offormula HM-L-NH₂ using the piperidone of formula VII and an analogousprocedure to one described in Example 1.h) or Example 3, parts a)-e).

For the preparation of a starting material piperidine of formula II, a1-protected 4-piperidone may be used for a reductive alkylation,followed by a cyclization similar to that described above in procedure(b), and finally deprotection, for example as described in Example 1,parts h)-j). Generally, a starting material piperidine of formula II maybe obtained from a 1-protected 4-aminopiperidine or a 1-protected4-piperidone using conventional synthetic methodology.

As will be clear to one skilled in the art, a variety of sequences isavailable for preparation of the starting materials, and the sequencesleading to the starting materials and products of the invention may bealtered if appropriate considerations regarding the synthetic methodsand radicals present are followed.

The utility of a Compound may be demonstrated by standard tests andclinical studies, including those described below.

Neurokinin A (NKA) Receptor-binding Assay (Test A)

The ability of a Compound to antagonize the binding of NKA at the NK2receptor may be demonstrated using an assay using the human NK2 receptorexpressed in Mouse Erythroleukemia (MEL) cells by using MEL cellmembranes (MELM) which bear high-affinity and selective NK2 receptorsand which is carried out as follows.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows construction of the MEL cell expression vector constructpMEG3/hNK2R.

FIG. 2 shows construction of the expression vector constructGSE1417/hNK2R.

FIG. 3 shows expression of human NK2 receptor in MEL C88 cells.

MEL Cell Expression of Human NK2 Receptor (hNK2R)

Heterologous protein expression in Mouse Erythroleukemia (MEL) cellsuses the human globin locus control region (LCR) (F. Grosveld et al.,Cell (1987) 51, 975-985). The cDNAs are inserted between the humanbeta-globin promoter and the second intron of the human beta-globingene, and this expression cassette is then placed downstream of the LCRand transfected into MEL cells (M. Needham et al., Nucl. Acids Res.(1992) 20, 997-1003). Human NK2 receptor cDNA (A. Graham et al.,Biochem. Biophys. Res. Commun. (1991) 177, 8-16) was isolated from humanlung RNA by polymerase chain reaction and DNA sequenced. Human NK2receptor cDNA was subcloned into a shuttle vector (pMEG3) containing thebeta-globin promoter and the 3′ portion of the human beta-globin gene(FIG. 1). Human NK2 receptor cDNA was restricted with Eco 0109 (5′ end)and Bam HI (3′ end). An oligonucleotide linker-adaptor containing aninternal Hind III site and a 3′ end Eco 0109 site was ligated to thehNK2R cDNA fragment. The sequence of the top strand oligonucleotide=5′d(GCGCAAGCTTATGGG) (SEQ ID NO:1) and the bottom strandoligonucleotide =5′d(GTCCCCATAAGCTTGCGC) (SEQ ID NO:2). These wereannealed and ligated to the hNK2R fragment by standard methods.Following cleavage with Hind III, the resulting fragment was cloned intothe Hind III and Bam HI sites in the polylinker of the shuttle vectorpMEG3. The construct (pMEG3/hNK2R) was verified by restriction mappingand sequencing the 5′ end and 3′ end junctions of cDNA/vector. This wasthen transformed into E.coli DH5 alpha, and plasmid DNA was isolated bystandard methods and verified by restriction mapping and DNA sequencing.A ClaI/Asp718 cassette carrying the beta-globin promoter, human NK2receptor cDNA and the 3′ beta-globin gene fragment was excised andsubcloned downstream of the LCR in plasmid pGSE1417 (FIG. 2). ThepMEG3/hKNK-2R construct was cleaved with ClaI and Asp7l8 and cloneddirectly into the ClaI and Asp718 sites (3′ of LCR) in the expressionvector GSE1417. The construct GSE1417/hNK2R (13.9kb) was verified byrestriction mapping. E.coli DH5 alpha was transformed and recombinantplasmids verified by restriction mapping. MEL C88 cells (A. Deisserothet al., Cell (1978) 15, 55-63) were electroporated (M. Antoniou, MethodsMolecular Biology (1991) 7, 421-434) with PvuI linearized pGSE1417/humanNK2 receptor DNA. Directly after transfection, cells were diluted inculture medium to 10⁴ and 10⁵ cell per mL and 1 mL aliquots transferredto each well of a 24-well plate.

G418 was added to a concentration of 1 mg/mL 24 hours after thetransfection to select for stable transfectants. Individual clones werepicked or pooled to generate populations seven to ten days after theaddition of selective medium. FIG. 3 shows the strategy used to isolatetransfected MEL/human NK2 receptor cell line. For expression studies,cells were maintained in exponential growth for a period of four days,and then dimethyl sulfoxide (DMSO) was added to a final concentration of2% (v/v) to induce differentation and hence expression. Samples weretaken 4 days post induction for mRNA and NKA binding analyses. Theresults indicated that clone #1 expresses hNK2R at the highest level(both hNK2R mRNA and specific NKA binding). This clone was scaled up andis now routinely fermented at 20 litre scale per month and supplied foruse in Test A.

Membrane preparations (MELM) prepared from the MEL cells containinghigh-affinity NK2 receptors were prepared according to a publishedprotocol (D. Aharony, et al., Neuropeptides (1992) 23, 121-130) with thefollowing minor modifications: (1) Iodoacetamide (1 mM) was included inthe homogenization buffer; (2) Homogenization was as published but for ashorter period of 10 seconds once and at a slower speed (setting 10);and (3) The equilibration step with KCl/EDTA was not performed. In atypical preparation, binding of ³H-NKA (2.5 nM) to MELM was highlyspecific (88±4%) and linearly dependent on the protein concentration,with significant binding detected as low as 26 μg protein/mL.Equilibrium-competion experiments demonstated binding to high-affinity,high-density receptors with K_(D)=1187 nM, B_(max)=2229 fmol/mg protein.

The radio ligand ³H-neurokinin A (³H-NKA) as [4,5-³H-Leu⁹]-NKA (typicalspecific activity, 117 Ci/mmol) is obtained by custom synthesis fromCambridge Research Biochemicals and is >95% pure. Repeated HPLC analysisdemonstrated that the ligand is stable under proper storage conditions(silanized vials with 0.2% mercaptoethanol, under argon). Also, nodegradation or metabolism is apparent in the receptor-binding assay.

The assay is carried out using an incubation buffer consisting of 50 mMTris HCl (pH 7.4), 5 mM Mg⁺⁺, 100 μM thiorphan, 1 ³H-NKA, 0.02% (w:v)BSA, 30 mM K⁺, and 300 μM dithiothreitol; and the concentration ofmembrane protein is held at approximately 0.05-0.025 mg per tube.Nonspecific binding is routinely defined with 1 μM NKA. Each tubereceives the following: 150 μL incubation buffer, 20 μL ³H-NKA, 20 μLCompound, NKA or buffer as appropriate, and 125 μL membrane suspension.The reaction is initiated by the addition of the membranes. The tubesare incubated for 60 min at 25° C. in a shaking water bath. The reactionis terminated by washing the tubes with 10 mL of ice-cold 50 mM Tris HClusing a Brandel cell harvesting system using Whatman GF/B filters whichhave been soaked at least 4 hours at room temperature in 0.01% (w:v)polyethylenimine to collect the membranes. The filters are deposited inscintillation vials and read in a Beckman LS 6000LL ScintillationCounter. The binding constant K_(i) is calculated by standard methodsand is typically the mean of several such determinations. The K_(i)values may be converted to negative logarithms and expressed as -logmolar K_(i) (i.e. pK_(i)).

In an initial use of this assay, the IC₅₀ measured for the standardcompound L-659,877 was found to be 30 nM versus ³H-NKA binding to MELM.The selectivity of a Compound for binding at the NK2 receptor may beshown by determining its binding at other receptors using standardassays, for example, one using a tritiated derivative of SP in a tissuepreparation selective for NK1 receptors or one using a tritiatedderivative of NKB in a tissue preparation selective for NK3 receptors.

Guinea Pig Assay (Test B)

In the test described below either NKA or [β-Ala⁸]-NKA(4-10) is used asan agonist. The chosen agonist is refered to as AG throughout thedescription. The ability of a Compound to antagonize the action of AG ina pulmonary tissue may be demonstrated using a functional assay inguinea pig trachea, which is carried out as follows.

Male guinea pigs are killed by a sharp blow to the back of the head. Thetrachea are removed, trimmed of excess tissue and divided into twosegments. Each segment is suspended as a ring between stainless steelstirrups in water-jacketed (37.5° C.) tissue baths containing aphysiological salt solution of the following composition (mM): NaCl,119; KCl 4.6; CaCl₂, 1.8; MgCl₂, 0.5; NaH₂PO₄, 1; NaHCO₃, 25; glucose,11; thiorphan, 0.001; and indomethacin, 0.005; gassed continuously with95% O₂-%5 CO₂. Initial tension placed on each tissue is 1 g, which ismaintained throughout a 0.5 to 1.5 hour equilibration period beforeaddition of other drugs. Contractile responses are measured on a Grasspolygraph via Grass FT-03 force transducers.

Tissues are challenged repetitively with a single concentration of AG(10 nM) with intervening 30 min periods with washing to allow thetension to return to baseline levels. The magnitude of the contractionsto AG reaches a constant level after two challenges, and each Compoundis tested for inhibition of responses to AG by addition to the tissuebath 15 minutes before the third or subsequent exposure to the agonist.The contractile response to AG in the presence of Compound is comparedto that obtained with the second AG challenge (in the absence ofCompound). Percent inhibition is determined when a Compound produces astatistically significant (p<0.05) reduction of the contraction and iscalculated using the second contractile response as 100%.

Potencies of selected Compounds are evaluated by calculating apparentdissociation constants (K_(B)) for each concentration tested using thestandard equation:

K_(B)=[antagonist]/(dose ratio−1)

where dose ratio=antilog[(AG −log molar EC₅₀ without Compound) −(AG−logmolar EC₅₀ with Compound)]. The K_(B) values may be converted to thenegative logarithms and expressed as −log molar K_(B) (i.e. PK_(B)). Forthis evaluation, complete concentration-response curves for AG areobtained in the absence and presence of Compound (30 min incubationperiod) using paired tracheal rings. The potency of AG is determined at50% of its own maximum response level in each curve. The EC₅₀ values areconverted to the negative logarithms and expressed as −log molar EC₅₀.Maximum contractile responses to AG are determined by expressing themaximum response to AG as a percentage of the contraction caused bycarbachol (30μM), added after the initial equilibration period. When astatistically significant (p<0.05) reduction of the maximum response toAG is produced by a Compound, the percent inhibition is calculatedrelative to the percentage of carbachol contraction in the untreated,paired tissue used as 100%.

Clinical studies to demonstrate the efficacy of a Compound may becarried out using standard methods. For example, the ability of aCompound to prevent or treat the symptoms of asthma or asthma-likeconditions may be demonstrated using a challenge of inhaled cold air orallergen and evaluation by standard pulmonary measurements such as, forexample, FEV₁ (forced expiratory volume in one second) and FVC (forcedvital capacity), analyzed by standard methods of statistical analysis.

It will be appreciated that the implications of a Compound's activity inTest A or Test B is not limited to asthma, but rather, that the testprovides evidence of general antagonism of NKA. In general, theCompounds which were tested demonstrated statistically significantactivity in Test A with a K_(i) of 1 μM or much less. For example, thecompound described in Example 2 was typically found to have a K_(i) of4.1 nM. In Test B, a pK_(B) of 5 or greater was typically measured for aCompound. For example, a pK_(B) of 8.7 was measured for the compounddescribed in Example 2. It should be noted that there may not always bea direct correlation between the activities of Compounds measured asK_(i) values in Test A and the values measured in other assays, such asthe pK_(B) measured in Test B.

As discussed above, Compounds of the invention possesses NKA antagonistproperties. Accordingly, they antagonizes at least one of the actions ofNKA which are known to include bronchoconstriction, increasedmicrovascular permeability, vasodilation and activation of mast cells.Accordingly, one feature of the invention is the use of a compound offormula I; or the N-oxide of said compound of formula I at thepiperidino nitrogen indicated by Δ; or a pharmaceutically acceptablesalt of said compound of formula I or said N-oxide; or a quaternaryammonium salt of said compound of formula I in which the piperidinonitrogen indicated by Δ is a quadricovalent ammonium nitrogen whereinthe fourth radical on the nitrogen is (1-4C)alkyl or benzyl and theassociated counterion is a pharmaceutically acceptable anion; as definedabove, in the treatment of a disease in a human or other mammal in needthereof in which NKA is implicated and antagonism of its action isdesired, such as for example the treatment of asthma or a relateddisorder. In addition, another feature of the invention is provided bythe use of a compound of formula I; or the N-oxide of said compound offormula I at the piperidino nitrogen indicated by Δ; or apharmaceutically acceptable salt of said compound of formula I or saidN-oxide; or a quaternary ammonium salt of said compound of formula I inwhich the piperidino nitrogen indicated by Δ is a quadricovalentammonium nitrogen wherein the fourth radical on the nitrogen is(1-4C)alkyl or benzyl and the associated counterion is apharmaceutically acceptable anion; as defined above, as apharmacological standard for the development and standardization of newdisease models or assays for use in developing new therapeutic agentsfor treating the diseases in which NKA is implicated or for assays fortheir diagnosis.

When used in the treatment of such a disease, a Compound is generallyadministered as an appropriate pharmaceutical composition whichcomprises a compound of formula I; or the N-oxide of said compound offormula I at the piperidino nitrogen indicated by Δ; or apharmaceutically acceptable salt of said compound of formula I or saidN-oxide; or a quaternary ammonium salt of said compound of formula I inwhich the piperidino nitrogen indicated by α is a quadricovalentammonium nitrogen wherein the fourth radical on the nitrogen is(1-4C)alkyl or benzyl and the associated counterion is apharmaceutically acceptable anion; as defined above, and apharmaceutically acceptable diluent or carrier, the composition beingadapted for the particular route of administration chosen. Such acomposition is provided as a further feature of the invention. It may beobtained employing conventional procedures and excipients and binders,and it may be one of a variety of dosage forms. Such forms include, forexample, tablets, capsules, solutions or suspensions for oraladministration; suppositories for rectal administration; sterilesolutions or suspensions for administration by intravenous orintramuscular infusion or injection; aerosols or nebulizer solutions orsuspensions for administration by inhalation; or powders together withpharmaceutically acceptable solid diluents such as lactose foradministration by insufflation.

For oral administration a tablet or capsule containing up to 250 mg (andtypically 5 to 100 mg) of a compound of formula I may conveniently beused. For administration by inhalation, a compound of formula I will beadministered to humans in a daily dose range of, for example, 5 to 100mg, in a single dose or divided into two to four daily doses. Similarly,for intravenous or intramuscular injection or infusion a sterilesolution or suspension containing up to 10% w/w (and typically 0.05 to5% w/w) of a compound of formula I may conveniently be used.

The dose of a compound of formula I to be administered will necessarilybe varied according to principles well known in the art taking accountof the route of administration and the severity of the condition and thesize and age of the patient under treatment. However, in general, thecompound of formula I will be administered to a warm-blooded animal(such as man) so that a dose in the range of, for example, 0.01 to 25mg/kg (and usually 0.1 to 5 mg/kg) is received. It will be understoodthat generally equivalent amounts of an N-oxide or a pharmaceuticallyacceptable salt or a quaternary ammonium salt of a compound of formula Imay be used.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;

(ii) organic solutions were dried over anhydrous sodium sulfate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

(iii) chromatography means ′ flash chromatography′ (method of Still)carried out on Merck Kieselgel (Art 9385 from E. Merck, Darmstadt,Germany); reversed phase silica gel means octadecylsilane (ODS) coatedsupport having a particle diameter of 32-74μ, known as “PREP-40-ODS”(Art 731740-100 from Bodman Chemicals, Aston, Pa., USA); thin layerchomatography (TLC) was carried out on 0.25 mm silica gel GHLF plates(Art 21521 from Analtech, Newark, Del., USA);

(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

(v) melting points are uncorrected and (d) indicates decomposition; themelting points given are those obtained for the materials prepared asdescribed; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(vi) final products had satisfactory nuclear magnetic resonance (NMR)spectra and were substantially pure by TLC;

(vii) yields are given for illustration only and are not necessarilythose which may be obtained by diligent process development;preparations were repeated if more material was required;

(viii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHzusing CDCl₃ as solvent; conventional abbreviations for signal shape areused; for AB spectra the directly observed shifts are reported.

(ix) chemical symbols have their usual meanings; SI units symbols areused;

(x) reduced pressures are given as absolute pressures in pascals (Pa);elevated pressures are given as gauge pressures in bars;

(xi) solvent ratios are given in volume: volume (v/v) terms; and

(xii) mass spectra (MS) were run with an electron energy of 70 electronvolts in the chemical ionizaton mode using a direct exposure probe;generally, only peaks which indicate the parent mass are reported.

EXAMPLE 1N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxo-1,3-oxazolidin-3-yl)piperidino]butyl]-N-methylbenzamidehydrochoride

N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.823 g) inmethanol (4 mL) was added to a solution of4-(2-oxo-1,3-oxazolidin-3-yl)piperidine (0.600 g) and acetic acid (0.20mL) in methanol (8 mL). After 5 minutes, sodium cyanoborohydride (0.220g) in methanol (4 mL) was added in a single portion. After being stirredfor 3 hours, the reaction mixture was diluted with aqueous sodiumbicarbonate, stirred for 30 minutes, and extracted with dichloromethane.The organic extracts were dried, evaporated, and chromatographed, withdichloromethane:methanol (gradient 98:2, 90:10) as eluent. The resultingmaterial was dissolved in dichloromethane, precipitated as thehydrochloride salt with ethereal hydrogen chloride, evaporated, andplaced under high vacuum overnight to give the title compound as a whitesolid (0.88 g); MS: m/z=504(M+1); Analysis for C₂₆H₃₁Cl₂N₃O₃.1.20 HCl:Calculated: C, 56.96; H, 5.92; N, 7.66; Found: C, 57.02; H, 6.05; N,7.62.

The intermediate N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamidewas prepared as follows.

a. 1-Bromo-2-(tetrahydropyran-2-yloxy)ethane. To a mechanically stirredsolution of dihydropyran (1 L) and a strong acid ion exchange resin(10.0 g) in hexane (2 L) was added 2-bromoethanol (985 g) dropwise overa period of 1.5 hours in a cold water bath to maintain an internaltemperature of 35-40° C. After being stirred overnight at roomtemperature, the reaction mixture was chromatographed with hexane (6 L).The eluate was evaporated to give an amber liquid which was distilledthrough a 2 inch vigreux column, collecting the material boiling between75-95° C. (3,300-4,700 Pa). This material was redistilled to give theether as an oil (1195.5 g); bp 80-90° C. (2666 Pa); NMR: 4.68 (m,1),4.01 (m,1), 3.89 (m,1), 3.77 (m,1), 3.52 (m,3), 1.75-1.50 (m,6).

b. α-[2-(Tetrahydropyran-2-yloxy)ethyl]-3,4-dichlorophenyl-acetonitrile.To a solution of sodium hydride (218.0 g of a 55% oil suspension) intetrahydrofuran (4 L) at 10° C. in an ice/water bath was added3,4-dichlorophenylacetonitrile (893.0 g) in tetrahydrofuran (2 L) over aperiod of 45 minutes, and the resulting solution was allowed to stir for2 hours at room temperature. The mixture was cooled in an ice/waterbath, and 1-bromo-2-(tetrahydropyran-2-yloxy)ethane (1076.0 g) wasdropped in as a neat oil over a period of 25 minutes. The mixture wasstirred overnight at room temperature and divided into four 2-literportions. Each portion was diluted with saturated ammonium chloride (3L) and extracted with ether (500 mL). The combined organic layers werewashed with aqueous ammonium chloride, dried, and evaporated. Theresulting material was chromatographed, with hexane:dichloromethane(gradient 100:0, 0:100) as eluent, to give the nitrile as an oil (932g); NMR: 7.47 (m,4), 7.20 (m,2), 4.57 (m,2), 4.08 (m,2), 3.85 (m,4),3.54 (m,3), 3.37 (m,1), 2.15 (m,4), 1.77 (m,4), 1.56 (m,8).

c. 2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl-amine. To asolution of the above nitrile (128.3 g) in 95% ethanol (1.1 L) andconcentrated ammonium hydroxide (550 mL) was added Raney Nickel (25.0g). The mixture was hydrogenated under a hydrogen atmosphere at 3.6 barsfor 1.5 days. The mixture was filtered through diatomaceous earth toremove the catalyst, and the resulting filtrate was evaporated. Theresulting material was chromatographed, with dichloromethane:methanol(gradient 100:0, 95:5) as eluent, to give the amine as an oil (91 g);NMR: 7.40 (s,1), 7.38 (s,1), 7.32 (d,1, J=2.1), 7.28 (d,1, J=2.0), 7.07(dd,1, J=2.1, 4.9), 7.04 (dd,1, J=2.1, 4.9), 4.50 (m,1), 4.43 (m,1),3.70 (m,4), 3.45 (m,2), 3.27 (m,1), 3.17 (m,1), 2.97-2.75 (m,6), 2.00(m,2), 1.82-1.66 (m,6), 1.53 (m,8), 1.18 (broad s,4); MS: m/z=318(M+1).

d.N-[2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]-benzamide.To a solution of the amine (2.5 g) in dichloromethane (35 mL) was addedtriethylamine (1.1 mL) and benzoic anhydride (1.85 g), and the resultingsolution was allowed to stir for 45 minutes. The mixture was washed with0.2 N hydrochloric acid, 1 N sodium hydroxide, and water, dried, andevaporated to give the amide as an oil (3.3 g); NMR: 7.63 (m,4), 7.46(m,2), 7.37 (m,8), 7.09 (m,2), 6.22 (m,2), 4.50 (m,1), 4.43 (m,1), 3.8(m,5), 3.63 (m,1), 3.5 (m,4), 3.36 (m,1), 3.23 (m,1), 3.11 (m,2), 2.06(m,2), 1.90-1.77 (m,4), 1.68 (m,2), 1.51 (m,8); MS:m/z=338[(M+1)-tetrahydropyranyl].

e.N-[2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yl-oxy)butyl]-N-methylbenzamide.To a solution of the above amide (3.3 g) in dimethylsulfoxide (20 mL)was added powdered potassium hydroxide (1.6 g), followed by iodomethane(1.0 mL) after 15 minutes. After 1 hour, the mixture was diluted withwater and extracted with dichloromethane. The combined organic extractswere dried and evaporated to give the amide as an oil (3.1 g); MS:m/z=352[(M+1)-tetrahydropyranyl].

f. N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide.

To a solution of the above amide (10.5 g) in tetrahydrofuran (100 mL)was added 6 N hydrochloric acid (50 mL), and the resulting solution wasallowed to stir overnight. The mixture was neutralized with 10 N sodiumhydroxide, diluted with water, and extracted with dichloromethane. Theorganic layer was dried and evaporated. The resulting yellow solid wassuspended in ether and filtered to give the alcohol as a white solid(8.4 g); MS: m/z=352(M+1).

g. N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide. To asolution of oxalyl chloride (2.6 mL) in dichloromethane (60 mL) at −78°C. was added dimethylsulfoxide (4.2 mL) in dichloromethane (30 mL),followed by the above alcohol (8.3 g) in dimethylsulfoxide (6 mL) anddichloromethane (30 mL). The resulting solution was allowed to stir for30 minutes, and triethylamine (16.4 mL) was added. The mixture wasallowed to warm to room temperature, diluted with dichloromethane,washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate,and water, dried, and evaporated. The resulting yellow solid wassuspended in ether and filtered to give the the aldehyde as a whitesolid (6.4 g); MS: m/z=350(M+1).

The intermediate 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine was prepared asfollows.

h. 1-Benzyloxycarbonyl-4-(2-hydroxyethylamino)piperidine.1-Benzyloxycarbonyl-4-oxopiperidine (2.5 g) in methanol (7.0 mL) wasadded to a solution of ethanolamine (1.3 mL) and acetic acid (1.2 mL) inmethanol (20 mL). After 5 minutes, sodium cyanoborohydride (1.35 g) inmethanol (6 mL) was added in a single portion. After being stirredovernight, the reaction mixture was diluted with aqueous sodiumbicarbonate, stirred for 30 minutes, and extracted with dichloromethane.The combined organic extracts were evaporated, dissolved in 1 Nhydrochloric acid, and washed with dichloromethane. The aqueous phasewas basified with 1 N sodium hydroxide and extracted withdichloromethane. The extracts were dried and evaporated to give theamino alcohol as an oil (1.7 g); NMR (CD₃OD): 7.34 (m,5), 5.10 (s,2),4.13 (m,2), 3.64 (m,2), 2.86 (m,2), 2.73 (m,2), 2.67 (m,1), 1.90 (m,2),1.25 (m,2); MS: m/z=279(M+1).

i. 1-Benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine. Asolution of the amino alcohol (1.7 g) and 1,1′-carbonyldiimidazole (2.4g) in chloroform (30 mL) was heated at reflux for 6 hours. The reactionmixture was diluted with dichloromethane and washed with 1 N sodiumhydroxide and water. The separated organic phase was dried andevaporated to give the oxazolidin-3-yl piperidine as a viscous oil (1.9g); NMR: 7.35 (m,5), 5.13 (s,2), 4.34 (m,4), 3.89 (m,1), 3.49 (m,2),2.86 (m,2), 1.78 (m,2), 1.58 (m,2); MS: m/z=305(M+1).

j. 4-(2-Oxo-1,3-oxazolidin-3-yl)piperidine. A solution of the aboveoxazolidin-3-ylpiperidine (1.85 g) and 20% palladium hydroxide on carbon(0.340 g) in ethanol (30 mL) was stirred overnight under 1 bar ofhydrogen. The reaction mixture was filtered through diatomaceous earthand the filtrate was evaporated to give the title compound (0.950 g) asa white solid; NMR (CD₃OD): 4.35 (m,2), 3.75 (m,1), 3.62 (m,2), 3.20(m,2), 2.76 (m,2), 1.75 (m,4);

MS: m/z=171(M+1).

EXAMPLE 2(S)-N-[2-(3,4-Dichlorophenyl)-4-(2-oxoperhydro-1,3-oxa-zin-3-yl)piperidino]butyl]-N-methylbenzamidehydrochloride

Using the procedure of Example 1, replacing4-(4-(2-oxo-1,3-oxa-zolidin-3-yl)piperidine with4-(2-oxoperhydro-1,3-oxazin-3-yl)-piperidine, andN-[-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-benzamide by the(S)-enantiomer, the title compound was obtained as a white solid; MS:m/z=518(M+1); Analysis for C₂₇H₃₃Cl₂N₃O₃.1.55 HCl.0.20 (C₂H₅)₂O:Calculated: C, 56.61; H, 6.24; N, 7.12; Found: C, 56.54; H, 6.60; N,7.38.

The (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl-N-methyl-benzamide wasprepared as follows.

a. 2-(3,4-Dichlorophenyl)-4-hydroxybutylamine. To a mechanically stirredsolution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine(550 g) in methanol (3300 mL) was added in one portion 6.0 Nhydrochloric acid (352 mL), resulting in a slight exotherm. After beingstirred for 3 hours, the reaction mixture was evaporated, and theresidue was diluted with water to 3 L volume. This solution wasextracted with ether (2 times 500 mL), basified with sodium hydroxidepellets (100 g), and extracted with ethyl acetate (4 times 500 mL). Thecombined ethyl acetate extracts were washed (800 mL saturated sodiumchloride), dried, and evaporated to give the alcohol as an amber oil(367 g) that solidified under high vacuum; NMR: 7.39 (d,1, J=8.2), 7.28(d,1, J=2.0), 7.04 (dd,1, J=8.2, 2.0), 3.65 (m,1), 3.50 (m,1), 2.90(m,2), 2.71 (m,1), 2.25 (m,2), 1.86 (m,2).

b. (S)-2-(3,4-Dichlorophenyl)-4-hydroxybutylamine. To a mechanicallystirred solution of D-tartaric acid (222 g) in methanol (4 L) at refluxwas added the above amino alcohol (342 g) in warm methanol (2 L) in oneportion and washed down with additional methanol (1 L). The mixture washeated to reflux. Crystals began to form before attaining the boilingpoint. After 1.5 hours at reflux, the solution was gradually cooled toroom temperature and stirred for 3 days. The first crop of tartrate saltwas collected by suction filtration and dried in a vacuum oven at 60° C.to give the product (232 g). This material was taken up in methanol(13.5 L) at boiling, and held at reflux for 1 hour allowing 1 L ofmethanol to distil off. The mixture was allowed to cool gradually toroom temperature and stirred for 4 days. The first crop of crystals wascollected by suction filtration and dried to give a solid (178.8 g). Themethanol filtrate was evaporated to approximately 3 L volume. Theresulting suspension was heated back to reflux to give a clear solutionthat was allowed to cool gradually to room temperature with stirring. Asecond crop of crystals (43.8 g) was collected. The combined crops ofresolved amino alcohol tartrates (222.6 g) were taken up in 1.0 N sodiumhydroxide (1.5 L) and extracted with dichloromethane (4 times 500 mL).The combined organic extracts were washed with brine, dried, andevaporated to give the optically enriched amino alcohol as an off-whitesolid (135.4 g); mp 80-2° C.; NMR (CD₃OD): 7.47 (d,1, J=8.3), 7.42 (d,₁,J=2.1), 7.17 (dd,1, J=8.2, 2.1), 3.47 (m,1), 3.34 (m,1), 2.83 (m,3),1.92 (m,1), 1.74 (m,1); MS: m/z=324(M+1).

c. Ethyl (S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-carbamate. Ethylchloroformate (25.5 g) was added dropwise over 20 minutes to amechanically stirred solution of the above amino alcohol (50.0 g) andtriethylamine (24.9 g) in dichloromethane (600 mL) cooled to −30° C. Theinternal temperature was maintained at −20 to −25° C. during theaddition. The reaction mixture was then allowed to warm gradually toroom temperature over a 4 hour period, and washed (1 N hydrochloricacid, saturated aqueous sodium bicarbonate, and saturated aqueous sodiumchloride). The separated dichloromethane phase was dried and evaporatedto give the carbamate as a yellow oil (65.3 g); NMR (CD₃OD): 7.44 (d,1,J=8.3), 7.38 (d,1, J=2.1), 7.15 (dd,1, J=8.3, 2.1), 3.99 (q,2, J=7.1),3.45 (m,1), 3.29 (m,3), 2.97 (m,₁), 1.92 (m,1), 1.75 (m,1), 1.16 (t,3,J=7.1); MS: m/z=306(M+1).

d. (S)-N-Methyl-2-(3,4-dichlorophenyl)-4-hydroxybutylamine. The abovecarbamate (65.3 g) in tetrahydrofuran (500 mL) was added dropwise over30 minutes to a mechanically stirred suspension of lithium aluminumhydride (16.0 g) in tetrahydrofuran (200 mL). The internal temperaturerose to 45° C. during the addition. The reaction mixture was heated atreflux for 1 hour, then cooled to room temperature and stirredovernight. The mixture was cooled in an ice bath, and saturated aqueoussodium sulfate (50 mL) was added dropwise over 45 minutes. After anadditional hour of stirring, solid anhydrous sodium sulfate (50 g) wasadded. After being stirred for 30 minutes, the mixture was filteredthrough diatomaceous earth, and the filtrate was evaporated to give themethylamine as a yellow oil (52.9 g); NMR: 7.37 (d,1, J=8.2), 7.27 (d,1,J=2.0), 7.01 (dd,1, J=8.2, 2.1), 3.69 (m,1), 3.53 (m,1), 3.40 (m,2),2.76 (m,3), 2.45 (m,3), 1.89 (m,2); MS: m/z=248(M+1).

e. (S)-N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide.Benzoyl chloride (31.5 g) in dichloromethane (200 mL) was added dropwiseover 45 minutes to a mechanically stirred solution of the above amine(52.9 g) and triethylamine (54.0 g) in dichloromethane (1 L) cooled inan ice bath to maintain an internal temperature of 5-8° C. The reactionmixture was allowed to stir for 3 hours at room temperature, and thenwashed (1 N hydrochloric acid, brine). The separated dichloromethanelayer was evaporated to give a yellow oil which was chromatographed,with dichloromethane:methanol (gradient 100:0, 95:5) as eluent, to givethe benzamide as a white solid (65.6 g); mp 123-5° C.; MS: m/z=352(M+1);[a]_(D)=−18.3° (c=2.46, CH₃OH).

f. (S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide. Theabove alcohol (12.9 g) in dichloromethane (150 mL) was cannulated into asolution of Dess-Martin periodinane (18.6 g) and tert-butanol (4.5 mL)in dichloromethane (150 mL). After being stirred for 5 minutes, thereaction mixture was diluted with ether (600 mL) and a solution ofsodium bicarbonate (19.7 g) and sodium thiosulfate pentahydrate (64.5 g)in water (825 mL). The biphasic system was vigorously stirred until bothlayers became clear (approximately 30 minutes). The separated organiclayer was washed (saturated aqueous sodium bicarbonate), dried, andevaporated. The crude material was chromatographed, withdichloromethane:ether (1:1) as eluent, to give the aldehyde as a whitesolid (9.7 g) by precipitation and filtration from ether; MS:m/z=350(M+1).

The intermediate 4-(2-oxoperhydro-1,3-oxazin-3-yl)piperidine wasprepared as follows.

g. 1-Benzyloxycarbonyl-4-(3-hydroxypropylamino)piperidine. Using theprocedure of Example 1.h, replacing ethanolamine with3-amino-1-propanol, the amino piperidine was obtained as an oil; NMR(CD₃OD): 7.35 (m,5), 5.10 (s,2), 4.12 (m,2), 3.62 (t,2, J=6.2), 2.86(m,2), 2.71 (m,2), 2.65 (m,1), 1.90 (m,2), 1.71 (m,2), 1.24 (m,2); MS:m/z=293(M+1).

h. 1-Benzyloxycarbonyl-4-(2-oxoperhydro-1,3-oxazin-3-yl)-piperidine.Using the procedure of Example 1.i, replacing1-benzyloxycarbonyl-4-(2-hydroxyethylaino)piperidine with1-benzyloxycarbonyl-4-(3-hydroxypropylamino)piperidine, the oxazin-3-ylpiperidine was obtained as an oil; NMR (CD₃OD): 7.35 (m,5), 5.11 (s,2),4.22 (m,5), 3.24 (m,2), 2.88 (m,2), 1.99 (m,2), 1.69 (m,4); MS:m/z=319(M+1).

i. 4-(2-Oxoperhydro-1,3-oxazin-3-yl)piperidine. Using the procedure ofExample 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-(2-oxoperhydro-1,3-oxazin-3-yl)piperidine, thedeprotected piperidine was obtained as an amorphous, white solid; NMR(CD₃OD): 4.24 (m,2), 4.12 (m,1), 3.32 (m,2), 3.22 (m,2), 2.78 (m,2),2.03 (m,2), 1.79 (m,4); MS: m/z=185(M+1).

EXAMPLE 3(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoimidazolidin-1-yl)piperidino]butyl]-N-methylbenzamidehydrochloride

A stirred solution of(S)-N-[4-[4-(2-aminoethylamino)-piperidino]-2-(3,4-dichlorophenyl)butyl3-N-methylbenzamide(0.356 g) and 1,1′-carbonyldiimidazole (0.157 g) in chloroform (6 mL)was heated at reflux for 2 hours. The reaction mixture was diluted withdichloromethane, washed (aqueous sodium bicarbonate), dried, evaporated,and chromatographed, with dichloromethane:methanol (gradient 98:2,90:10) as eluent. The resulting material was dissolved indichloromethane, precipitated as the hydrochloride salt with etherealhydrogen chloride, evaporated, and placed under high vacuum overnight togive the title compound as a white solid (0.244 g); MS: m/z=503(M+1);Analysis for C₂₆H₃₂Cl₂N₄O₂.1.70 HCl.0.20 (C₂H₅)₂O: Calculated: C, 55.47;H, 6.20; N, 9.65; Found: C, 55.47; H, 6.35; N, 9.44.

The intermediate(S)-N-]4-[4-(2-aminoethylamino)piperidino]-2-(3,4-dichloro-phenyl)butyl]-N-methylbenzamidewas prepared as follows.

a. 1-Benzyloxycarbonyl-4-(2-aminoethylamino)piperidine.1-Benzyloxycarbonyl-4-oxo-piperidine (12.0 g) in methanol (72 mL) wasadded to a stirred solution of ethylenediamine (5.2 mL) and acetic acid(8.8 mL) in methanol (72 mL). After 15 minutes, sodium cyanoborohydride(9.7 g) in methanol (72 mL) was added in a single portion. After beingstirred overnight, the reaction mixture was evaporated; and the residuewas dissolved in 1 N hydrochloric acid (100 mL). Concentratedhydrochloric acid was added dropwise and stirring was continued untilthe evolution of gas ceased. The acidic aqueous mixture was washed withdichloromethane, basified to pH 10 with 10 N sodium hydroxide, andextracted with dichloromethane. The dichloromethane extracts were driedand evaporated to give the diamine as a viscous oil (7.5 g); NMR(CD₃OD): 7.35 (m,5), 5.10 (s,2), 4.12 (m,2), 2.89 (m,2), 2.70 (m,5),1.90 (m,2), 1.24 (m,2); MS: m/z=278(M+1).

b.1-Benzyloxycarbonyl-4-[(2,2,2-trifluoroacetyl)[(2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidine.Trifluoroacetic anhydride (10.5 mL) was added to a solution of the abovediamine (7.5 g) in chloroform (90 mL). After being stirred overnight,the reaction mixture was cooled to 0° C.; and triethylamine (8.3 mL) wasdropped in. After 1 hour, the mixture was diluted with dichloromethane,washed (1 N hydrochloric acid, aqueous sodium bicarbonate), dried,evaporated, and chromatographed, with dichloromethane:methanol (98:2) aseluent, to give the trifluoroacetylated piperidine as a white foam (8.9g); NMR (CD₃OD): 7.35 (m,5), 5.12 (s,2), 4.28 (m,2), 3.95 (m,1), 3.48(m,4), 2.90 (m,2), 1.78 (m,4); MS: m/z=470(M+1).

c.4-[(2,2,2-Trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)-ethyl]amino]piperidine.Using the procedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoro-acetylamino)ethyl]amino]piperidine,the 1-deprotected piperidine was obtained as a yellow oil; NMR (CD₃OD):3.84 (m,1), 3.51 (m,4), 3.12 (m,2), 2.61 (m,2), 1.74 (m,4); MS:m/z=336(M+1).

d.(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-trifluoro-acetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]-butyl]-N-methylbenzamide.Using the procedure of Example 1, replacing4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidine,and N-[-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with the(S)-enantiomer, the N-methylbenzamide was obtained as a viscous oil; MS:m/z=669(M+1).

e.(S)-N-[4-[4-(2-Aminoethylamino)piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide.A solution of the crude product from Example 3.d. (2.5 g) in 20% aqueouspotassium hydroxide (8.5 mL) and methanol (11 mL) was stirred for 1hour. The reaction mixture was acidified to pH 2 with 1 N hydrochloricacid and washed 3 times with dichloromethane. The aqueous phase was thenbasified to pH 10 with 10 N sodium hydroxide and extracted withdichloromethane. The extracts were dried and evaporated to give thediamine as a viscous oil (1.8 g); MS: m/z=477(M+1).

EXAMPLE 4(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-thioxoimidazolidin-1-yl)piperidino]butyl]-N-methylbenzamidehydrochloride

Using the procedure of Example 3, replacing 1,1′-carbonyldiimidazolewith 1,1′-thiocarbonyldi-2(1H)-pyridone and stirring at room temperaturefor 1.5 hours instead of reflux, the title compound was obtained as awhite solid; MS: m/z=519(M+1); Analysis for C₂₆H₃₂Cl₂N₄OS.1.70 HCl.0.10(C₂H₅)₂O: Calculated: C, 53.84; H, 5.93; N, 9.51; Found: C, 53.89; H,5.89; N, 9.48.

EXAMPLE 5(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydro-pyrimidin-1-yl)piperidino]butyl]-N-methylbenzamidedihydrochloride

Using the procedure of Example 3, replacing(S)-N-[4-[4-(2-aminoethylamino)piperidino]-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamidewith(S)-N-[-4-[4-(3-aminopropylamino)piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide,the title compound was obtained as a white solid; MS: m/z=517(M+1);Analysis for C₂₇H₃₄Cl₂N₄O₂.2.60 HCl.0.13 (C₂H₅)₂O: Calculated: C, 53.14;H, 6.14; N, 9.00; Found: C, 53.14; H, 6.31; N, 9.16.

The intermediate(S)-N-[4-[4-(3-aminopropylamino)piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidewas prepared as follows.

a. 1-Benzyloxycarbonyl-4-(3-aminopropylamino)piperidine. Using theprocedure of Example 3.a, replacing ethylenediamine with1,3-diaminopropane, the piperidine was obtained as a viscous oil; MS:m/z=292(M+1); NMR (CD₃OD): 7.34 (m,5), 5.10 (s,2), 4.13 (m,2), 2.86(m,2), 2.65 (m,5), 1.90 (m,2), 1.65 (m,2), 1.23 (m,2).

b.1-Benzyloxycarbonyl-4-[2,2,2-trifluoroacetyl)-[3-(2,2,2-trifluoroacetylamino)propyl]amino]piperidine.Using the procedure of Example 3. b, replacing1-benzyloxycarbonyl-4-(2-amino-ethylamino)piperidine with1-benzyloxycarbonyl-4-(3-aminopropyl-amino)piperidine and addingtriethylamine to the solution before the addition of trifluoroaceticanhydride at 0° C., the trifluoroacetylated piperidine was obtained as aviscous oil; NMR: 7.36 (m,5), 5.14 (s,2), 4.35 (m,2), 3.93 (m,1), 3.35(m,4), 2.83 (m,2), 1.87-1.74 (m,6); MS: m/z=484(M+1).

c. 4-[(2,2,2-Trifluoroacetyl)[3-(2,2,2-trifluoroacetylamino)propyl]amino]piperidine. Using the procedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-[(2,2,2-trifluoroacetyl)-[3-(2,2,2-trifluoroacetylamino)propyl]amino]piperidine,the 1-deprotected piperidine was obtained as a viscous oil; NMR (CD₃OD):4.39 (m,1), 3.98 (m,1), 3.30 (m,3), 2.95 (m,₁), 2.82 (m,1), 2.65 (m,2),2.01 (m,2), 1.75 (m,2), 1.32 (m,2); MS: m/z=350(M+1).

d.(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-trifluoroacetyl)-[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]butyl]-N-methylbenzamide.Using the procedure of Example 1, replacing4-(2-oxo-1,3-oxazolidin-3-yl)piperidine by4-[(2,2,2-trifluoroacetyl)-[3-(2,2,2-trifluoroacetylamino)propyl]amino]piperidine,and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide by the(S)-enantiomer, the N-methylbenzamide was obtained; MS: m/z=683(M+1).

e.(S)-N-[4-[4-(3-Aminopropylamino)piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide.Using the procedure of Example 3.e, replacing(S)-N-[2-(3,4-dichlorophenyl)-4-[4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]-butyl]-N-methylbenzamidebyN-[2-(3,4-dichlorophenyl)-4-[4-[(2,2,2-trifluoroacetyl)[3-(2,2,2-trifluoroacetylamino)propyl]amino]-piperidino]butyl]-N-methylbenzamide,the diamine was obtained as a viscous oil; MS: m/z=491(M+1).

EXAMPLE 6(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-thioxoperhydro-pyrimidin-1-yl)piperidino]butyl]-N-methylbenzamidedihydrochloride

Using the procedure of Example 3, replacing 1,1′-carbonyldiimidazole by1,1′-thiocarbonyldiimidazole, replacing(S)-N-[4-[4-(2-aminoethylamino)piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamideby(S)-N-[4-[4-(3-aminopropylamino)-piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide,and stirring overnight at room temperature instead of reflux, the titlecompound was obtained as a white solid; MS: m/z=533(M+1); Analysis forC₂₇H₃₄Cl₂N₄OS.2.30 HCl.0.10 (C₂H₅)₂O: Calculated: C, 52.67; H, 6.01; N,8.96; Found: C, 52.57; H, 6.11; N, 8.84.

EXAMPLE 7(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(3-methyl-2-thioxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamidehydrochloride.

Using the procedure of Example 1, replacing4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with4-(3-methyl-2-thioxoperhydropyrimidin-1-yl)-piperidine, andN-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with the(S)-enantiomer, the title compound was obtained as a white solid; MS:m/z=547(M+1); Analysis for C₂₈H₃₆Cl₂N₄OS.1.70 HCl.0.10 (C₂H₅)₂O:Calculated: C, 55.28; H, 6.32; N, 9.08; Found: C, 55.21; H, 6.37; N,8.88.

The intermediate 4-(3-methyl-2-thioxoperhydropyrimidin-1-yl)piperidinewas prepared as follows.

a. 1-Benzyloxycarbonyl-4-(3-methylaminopropylamino)piperidine. Using theprocedure of Example 3.a, replacing ethylenediamine withN-methyl-1,3-propanediamine, the title compound was obtained as aviscous oil; MS: m/z=306(M+1); NMR (CD₃OD): 7.34 (m,5), 5.10 (s,2), 4.13(m,2), 2.86 (m,2), 2.70 (m,5), 2.47 (s,3), 1.91 (m,2), 1.73 (m,2), 1.24(m,2).

b.1-Benzyloxycarbonyl-4-(3-methyl-2-thioxoperhydropyrimidin-1-yl)piperidine.A solution of the diamine (3.0 g) and 1,1′-thiocarbonyldiimidazole (1.9g) in chloroform (70 mL) was refluxed for 1.5 hours and stirredovernight at ambient temperature. The reaction mixture was diluted withdichloromethane and washed sequentially with water, 1 N hydrochloricacid, and aqueous sodium bicarbonate. The separated organic phase wasdried, evaporated, and chromatographed, with dichloromethane:ether(80:20) as eluent, to give the thiourea as a white solid (1.4 g); MS:m/z=348(M+1); NMR (CD₃OD): 7.35 (m,5), 5.66 (m,1), 5.11 (s,2), 4.24(m,2), 3.35 (m,5), 3.22 (m,2), 2.88 (m,2), 1.92 (m,2), 1.72-1.55 (m,4).

c. 4-(3-Methyl-2-thioxoperhydropyrimidin-1-yl)piperidine.Trifluoromethanesulfonic acid (2.0 mL) was added to a solution of theabove piperidine (1.4 g) and anisole (1.4 mL) in dichloromethane (20 mL)at 0° C. After being stirred for 2 hours, the reaction mixture wasevaporated, dissolved in methanol, passed through a column of a weakbase ion exchange resin, evaporated, and chromatographed, withdichloromethane:methanol (gradient 98:2, 90:10) as eluent. The resultingmaterial was dissolved in dilute aqueous hydrochloric acid, extractedwith dichloromethane (discarded), and basified with sodium hydroxide.The aqueous phase was then extracted with dichloromethane and evaporatedto give the piperidine as a white solid (0.75 g); MS: m/z=214(M+1); NMR(CD₃OD): 5.53 (m,1), 3.36 (m,5), 3.29 (m,2), 3.08 (m,2), 2.64 (m,2),1.94 (m,2), 1.72-1.53 (m,4).

EXAMPLE 8(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxo-1,3-perhydrodiazepin-1-yl)piperidino]butyl]-N-methylbenzamide dihydrochloride

Using the procedure of Example 1, replacing4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with4-(2-oxo-1,3-perhydrodiazepin-1-yl)-piperidine, andN-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the titlecompound was obtained as a white solid; MS: m/z=531(M+1); Analysis forC₂₈H₃₆Cl₂N₄O₂.2.10 HCl.0.20 (C₂H₅)₂O: Calculated: C, 55.53; H, 6.48; N,8.99; Found: C, 55.70, H, 6.53; N, 8.91.

The intermediate 4-(2-oxo-1,3-perhydrodiazepin-1-yl)piperidine wasprepared as follows.

a. 1-Benzyloxycarbonyl-4-(4-aminobutylamino)piperidine. Using theprocedure of Example 3.a, replacing ethylenediamine with1,4-diaminobutane, the title compound was obtained as a viscous oil; MS:m/z=306(M+1); NMR (CD₃OD): 7.34 (m,5), 5.10 (s,2), 4.13 (m,2), 2.86(m,2), 2.63 (m,5), 1.90 (m,2), 1.51 (m,4), 1.23 (m,2).

b. 1-Benzyloxycarbonyl-4-(2-oxo-1,3-perhydrodiazepin-1-yl)piper idine. Asolution of the diamine (1.6 g) and 1,1′-carbonyldiimidazole (0.94 g) inchloroform (40 mL) was refluxed for 1 hour. The reaction mixture wasdiluted with dichloromethane and washed with water. The separatedorganic phase was dried, evaporated, and chromatographed, withdichloromethane:methanol (gradient 98:2, 90:10) as eluent, to give theurea as a white solid (0.36 g); MS: m/z=332(M+1); NMR (CD₃OD): 7.34(m,5), 5.09 (s,2), 4.21 (m,3), 3.25 (m,2), 3.13 (m,2), 2.85 (m,2), 1.58(m,6), 1.44 (m,2).

c. 4-(2-Oxo-1,3-perhydrodiazepin-1-yl)piperidine. Using the procedure ofExample 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-(2-oxo-1,3-perhydrodiazepin-1-yl)piperidine, thepiperidine was obtained as a white solid; MS: m/z=198(M+1); NMR (CD₃OD):4.16 (m,1), 3.29 (m,2), 3.21 (m,2), 3.11 (m,2), 2.65 (m,2), 1.62 (m,6),1.48 (m,2).

EXAMPLE 9(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxo-5,5-dimethyl-perhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide

(S)-N-[2-(3,4-dichlorophenyl)-4-oxopropyl]-N-methylbenzamide (0.622 g)in methanol (8.0 mL) was added to a solution of4-(2-oxo-5,5-dimethylperhydropyrimidin-1-yl)piperidine (0.400 g) andacetic acid (0.11 mL) in methanol (8.0 mL). After 5 minutes, sodiumcyanoborohydride (0.119 g) in methanol (8.0 mL) was added in a singleportion. After being stirred overnight, the reaction mixture was dilutedwith aqueous sodium bicarbonate, stirred for 30 minutes, and extractedwith dichloromethane. The separated organic layer was dried, evaporated,and chromatographed, with dichloromethane:methanol (95:5) as eluent. Theresulting oil, which began to crystallize upon standing, was suspendedin ether and filtered to give the title compound as a white solid (0.720g); MS: m/z=545(M+1); Analysis for C₂₉H₃₈Cl₂N₄O₂: Calculated: C, 63.84;H, 7.02; N, 10.26; Found: C, 63.95; H, 6.95; N, 10.15.

The intermediate 4-(2-oxo-5,5-dimethylperhydropyrimidin-1-yl)piperidinewas prepared as follows.

a. 1-Benzyloxycarbonyl-4-(3-amino-2,2-dimethylpropylamino)-piperidine.Using the procedure of Example 3. a, replacing ethylenediamine with2,2-dimethyl-1,3-propanediamine, the title compound was obtained as aviscous oil; NMR (CD₃OD): 7.34 (m,5), 5.10 (s,2), 4.08 (m,2), 2.93(m,2), 2.57 (m,1), 2.46 (s,2), 2.44 (s,2), 1.89 (m,2), 1.27 (m,2), 0.89(s,6).

b.1-Benzyloxycarbonyl-4-(2-oxo-5,5-dimethylperhydropyrimidin-1-yl)piperidine.A solution of the diamine (3.02 g) and 1,1′-carbonyldiimidazole (2.19 g)in chloroform (40 mL) was refluxed for 3 hours. The reaction mixture wasdiluted with dichloromethane and washed sequentially with 1 Nhydrochloric acid and aqueous sodium bicarbonate. The separated organicphase was dried, evaporated, triturated from ether, and filtered to givethe urea as a white solid (1.72 g); MS: m/z=346(M+1); NMR (CD₃OD): 7.34(m,5), 5.10 (s,2), 4.35 (m,1), 4.23 (m,2), 2.87 (m,6), 1.58 (m,4), 1.00(s,6).

C. 4-(2-Oxo-5,5-dimethylperhydropyrimidin-1-yl)piperidine. Using theprocedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-(2-oxo-5,5-dimethylperhydropyrimidin-1-yl)piperidine,the piperidine was obtained as a white solid; MS: m/z=212(M+1); NMR(CD₃OD).: 4.28 (m,1), 3.10 (m,2), 2.92 (m,2), 2.89 (m,2), 2.66 (m,2),1.59 (m,4), 1.03 (s,6).

EXAMPLE 10(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamidecitrate

(S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.883 g) inmethanol (10.0 mL) was added to a solution of4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine (0.498 g) and aceticacid (0.145 mL) in methanol (10.0 mL). After 5 minutes, sodiumcyanoborohydride (0.159 g) in methanol (10.0 mL) was added in a singleportion. After being stirred for 3.5 hours, the reaction mixture wasdiluted with aqueous sodium bicarbonate, stirred for 30 minutes, andextracted with dichloromethane. The separated organic layer was dried,evaporated, and chromatographed, with dichloromethane:methanol (95:5) aseluent. The resulting oil (0.970 g) and citric acid (0.352 g) weredissolved in methanol and evaporated to give the title compound as aglass which was scraped out as a white solid (1.27 g); MS: m/z=531(M+1);Analysis for C₂₈H₃₆Cl₂N₄O₂.1.10 C₆H₈O₇.0.30 H2O Calculated: C, 55.53; H,6.11; N, 7.48; Found: C, 55.55; H, 6.04; N, 7.46.

The intermediate 4-(3-methyl-2-oxoperhydropyrimidin-1-yl)-piperidine wasprepared as follows.

a. 1-Benzyloxycarbonyl-4-(2-oxoperhydropyrimidin-1-yl)-piperidine. Astirred solution of 1-benzyloxycarbonyl-4-(3-aminopropylamino)piperidine(10.1 g) and 1,1′-carbonyldiimidazole (6.2 g) in chloroform (250 mL) washeated at reflux for 2 hours. The mixture was washed with water, and theseparated organic phase was dried, evaporated, and chromatographed, withdichloromethane/methanol (90:10) as eluent, to give the urea as a whitesolid (7.4 g); MS:

m/z=318(M+1); NMR (CDCl₃): 7.35 (m,5), 5.12 (s,2), 4.75 (m,1), 4.50(m,1), 4.26 (m,2), 3.27 (m,2), 3.13 (m,2), 1.89 (m,2), 1.63 (m,4).

b. 1-Benzyloxycarbonyl-4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine. Potassium tert-butoxide (19.3 mL, 1 M in tetrahydrofuran)was added to a solution of1-benzyloxycarbonyl-4-(2-oxoperhydro-pyrimidin-1-yl)piperidine (3.06 g)in tetrahydrofuran (88 mL). Iodomethane (2.4 mL) was then added, and thereaction mixture was stirred for 30 minutes. The reaction mixture wasdiluted with dichloromethane, washed with water, and chromatographed,with dichloromethane:methanol (gradient 98:2, 90:10) as eluent. Theproduct was triturated from ether and filtered to give the N- methylcompound as a white solid (2.78 g); MS: m/z=332(M+1); NMR (CDCl₃): 7.34(m,5), 5.12 (s,2), 4.53 (m,1), 4.26 (m,2), 3.21 (m,2), 3.11 (m,2), 2.93(s,3), 2.86 (m,2), 1.91 (m,2), 1.60 (m,4).

c. 4-(3-Methyl-2-oxoperhydropyrimidin-1-yl)piperidine. Using theprocedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine,the piperidine was obtained as a viscous oil; MS: m/z=198(M+1); NMR(CD₃OD): 4.19 (m,1), 3.14 (m,4), 2.98 (m,2), 2.80 (s,3), 2.53 (m,2),1.82 (m,2), 1.48 (m,4).

EXAMPLE 11(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(3-ethyl-2-oxoperhydro-pyrimidin-1-yl)piperidino]butyl]-N-methylbenzamidecitrate.

Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)piperidine, the title compoundwas obtained as a white solid; MS: m/z=545(M+1); Analysis forC₂₉H₃₈Cl₂N₄O₂.1.00 C₆H₈O₇: Calculated: C, 56.98; H, 6.28; N, 7.59;Found: C, 56.66; H, 6.31; N, 7.57.

The intermediate 4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)-piperidine wasprepared as follows.

a.1-Benzyloxycarbonyl-4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)-piperidine.Using the procedure of Example 10.b, replacing iodomethane withiodoethane, the benzyloxycarbonyl compound was obtained as a white solidby trituration with ether; MS: m/z=346(M+1); NMR (CDCl₃): 7.34 (m,5),5.12 (s,2), 4.54 (m,1), 4.26 (m,2), 3.38 (q,2, J=7.1), 3.22 (m,2), 3.11(m,2), 2.86 (m,2), 1.90 (m,2), 1.60 (m,4), 1.10 (t,3, J=7.1).

b. 4-(3-Ethyl-2-oxoperhydropyrimidin-1-yl)piperidine. Using theprocedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-(3-ethyl-2-oxoperhydropyrimidin-1-yl)piperidine,the piperidine was obtained as a viscous oil; MS: m/z=212(M+1); NMR(CDCl₃): 4.45 (m,1), 3.38 (q,2, J=7.1), 3.17 (m,6), 2.72 (m,2), 2.15(m,1), 1.91 (m,2), 1.62 (m,4), 1.10 (t,2, J=7.1).

EXAMPLE 12(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[3-(N,N-dimethyl-carbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidino]butyl]-N-methylbenzamidecitrate

Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-[3-(N,N-dimethyl-carbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the title compound was obtained as a white solid; MS: m/z=602(M+1);Analysis for C₃₁H₄₁Cl₂N₅O₃.1.10 C₆H₈O₇: Calculated: C, 55.48; H, 6.16;N, 8.60; Found: C, 55.22; H, 6.26; N, 8.65.

The intermediate4-[3-(N,N-dimethylacetamido)-2-oxoperhydropyrimidin-1-yl]piperidine wasprepared as follows:

a.1-Benzyloxycarbonyl-4-(3-carboxymethyl-2-oxoperhydropyrimidin-1-yl)piperidine.Potassium tert-butoxide (52 mL, 1 M in tert-butanol) was added tol-benzyloxycarbonyl-4-(2-oxoperhydropyrimidin-1-yl)piperidine (15.0 g),and the solution was stirred for 35 minutes. tert-Butyl bromoacetate(7.65 mL) was then added, and the mixture was stirred overnight. Thereaction mixture was diluted with tetrahydrofuran (20 mL) anddichloromethane (10 mL) followed by the addition of tetrabutylammoniumiodide (1.74 g), potassium tert-butoxide (52 mL, 1 M in tert-butanol),and tert-butyl bromoacetate (7.65 mL). After being stirred overnight,the reaction mixture was diluted with dichloromethane and washed withwater. The separated organic layer was dried, evaporated to an oil, anddissolved in 1 N hydrochloric acid (700 mL), tetrahydrofuran (200 mL),and methanol (200 mL). After being stirred overnight, the reactionmixture was concentrated in vacuo to remove the organic solvents. Theresulting aqueous solution was extracted with dichloromethane, acidifiedwith 2 N hydrochloric acid to a pH of 2, and extracted withdichloromethane. The first organic extract was concentrated to giveunreacted 1-benzyloxycarbonyl-4-(2-oxoperhydropyrimidin-1-yl)piperidine(7.0 g). The second organic extract was washed with water, dried, andevaporated. The crude product was triturated from ether and filtered togive the title compound as a white solid (8.3 g); MS: m/z=376(M+1); NMR(CDCl₃): 7.35 (m,5), 5.12 (s,2), 4.48 (m,1), 4.28 (m,2), 4.02 (s,2),3.35 (m,2), 3.18 (m,2), 2.87 (m,2), 1.97 (m,2), 1.65 (m,4).

b.1-Benzyloxycarbonyl-4-[3-(N,N-dimethylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine.A solution of1-benzyloxycarbonyl-4-(3-carboxymethyl-2-oxoperhydropyrimidin-1-yl)-piperidine(2.00 g), dimethylamine hydrochloride (0.522 g), triethylamine (0.89mL), 4-dimethylaminopyridine (0.781 g), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.23 g) indichloromethane (55 mL) was stirred overnight. The reaction mixture waswashed (1 N hydrochloric acid, aqueous sodium bicarbonate), dried, andevaporated. The crude product was chromatographed, withdichloromethane:methanol (gradient 98:2, 80:20) as eluent, trituratedfrom ether, and filtered to give the amide as a white solid (2.00 g);MS: m/z=403(M+1); NMR (CDCl₃): 7.35 (m,5), 5.12 (s,2), 4.50 (m,1), 4.27(m,2), 4.12 (m,2), 3.35 (m,2), 3.18 (m,2), 3.01 (s,3), 2.95 (s,3), 2.84(m,2), 1.98 (m,2), 1.64 (m,4).

c. 4-[3-(N,N-Dimethylacetamido)-2-oxoperhydropyrimidin-1-yl]-piperidine.Using the procedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-[3-(N,N-dimethylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the piperidine was obtained as a white solid by trituration from ether;MS: m/z=269(M+1); NMR (CDCl₃): 4.40 (m,1), 4.12 (s,2), 3.35 (m,2), 3.24(m,2), 3.11 (m,2), 3.02 (s,3), 2.95 (s,3), 2.69 (m,2), 2.14 (m,1), 1.98(m,2), 1.64 (m,4).

EXAMPLE 13(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[3-(N-methylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidino]butyl]-N-methylbenzamidecitrate

Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-[3-(N-methylcarbamoyl-methyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the title compound was obtained as a white solid; MS: m/z=588(M+1);Analysis for C₃₀H₃₉Cl₂N₅O₃.1.10 C₆H₈O₇.0.40 H₂O: Calculated: C, 54.46;H, 6.06; N, 8.67; Found: C, 54.49; H, 6.10; N, 8.64.

The intermediate4-[3-(N-methylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]-piperidinewas prepared as follows.

a.1-Benzyloxycarbonyl-4-[3-(N-methylacetamido)-2-oxoperhydropyrimidin-1-yl]piperidine.Using the procedure of Example 12. b, replacing dimethylaminehydrochloride with methylamine hydrochloride, the amide was obtained asa gum; MS: m/z=389(M+1); NMR (CDCl₃): 7.35 (m,5), 6.59 (m,1), 5.12(s,2), 4.47 (m,1), 4.28 (m,2), 3.92 (s,2), 3.34 (m,2), 3.16 (m,2), 2.86(m,2), 2.80 (s,1.5), 2.79 (s,1.5), 1.96 (m,2), 1.63 (m,4).

b.4-[3-(N-Methylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]-piperidine.Using the procedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-[3-(N-methylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the piperidine was obtained as a gum; MS: m/z=255(M+1); NMR (CDCl₃):6.70 (m,1), 4.38 (m,1), 3.92 (s,2), 3.35 (m,2), 3.23 (m,2), 3.14 (m,2),2.81 (s,1.5), 2.79 (s,1.5), 2.72 (m,2), 2.10 (m,1), 1.97 (m,2), 1.64(m,4).

EXAMPLE 14(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[3-(N-benzylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidino]butyl]-N-methylbenzamidecitrate

Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-[3-(N-benzylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the title compound was obtained as a white solid; MS: m/z=664(M+1);Analysis for C₃₆H₄₃Cl₂N₅O₃.1.10 C₆H₈O₇.0.60 H₂O: Calculated: C, 57.69;H, 6.02; N, 7.89; Found: C, 57.65; H, 6.00; N, 7.90.

The intermediate4-[3-(N-benzylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]-piperidinewas prepared as follows:

a.1-Benzyloxycarbonyl-4-[3-(N-benzylcarbamoylmethyl)-2-oxoperhydro-pyrimidin-1-yl]piperidine.Using the procedure of Example 12. b, replacing dimethylaminehydrochloride with benzylamine and omitting triethylamine, the amide wasobtained as a gum; MS: m/z=465(M+1); NMR (CD₃OD): 7.34 (m,5), 7.28(m,5), 5.10 (s,2), 4.38 (s,2), 4.33 (m,1), 4.22 (m,2), 3.99 (s,2), 3.30(m,2), 3.20 (m,2), 2.85 (m,2), 1.95 (m,2), 1.60 (m,4).

b.4-[3-(N-Benzylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]-piperidine.Using the procedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-[3-(N-benzylcarbamoylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the piperidine was obtained as a viscous oil; MS: m/z=331(M+1); NMR(CD₃OD): 7.29 (m,5), 4.39 (s,2), 4.30 (m,1), 4.00 (s,2), 3.30 (m,4),3.16 (m,2), 2.73 (m,2), 1.98 (m,2), 1.68 (m,4).

EXAMPLE 15(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[3-(ethoxycarbonylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidino]butyl]-N-methylbenzamidecitrate

Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-[3-(ethoxycarbonylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine, thetitle compound was obtained as a white solid; MS: m/z=603(M+1); Analysisfor C₃₁H₄₀Cl₂N₄O₄.1.10 C₆H₈O₇: Calculated: C, 55.41; H, 6.04; N, 6.88;Found: C, 55.28; H, 6.11; N, 6.86.

The intermediate4-[3-(ethoxycarbonylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine wasprepared as follows.

a.1-Benzyloxycarbonyl-4-[3-(ethoxycarbonylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine.A solution of1-benzyloxycarbonyl-4-(3-carboxymethyl-2-oxoperhydropyrimidin-1-yl)piperidine(1.51 g), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.64 g), andammonium bicarbonate (1.43 g) in chloroform (30 mL) was stirred for 4hours. The reaction mixture was diluted with dichloromethane, washedwith 1 N hydrochloric acid (5 times), dried, and evaporated. The crudeproduct was chromatographed, with dichloromethane:methanol (gradient98:2, 90:10) as eluent, and triturated from ether to give the ester as awhite solid (1.25 g); MS: m/z=404(M+1); NMR (CDCl₃): 7.34 (m,5), 5.11(s,2), 4.49 (m,1), 4.26 (m,2), 4.18 (q,2, J=7.1), 4.06 (s,2), 3.31(m,2), 3.17 (m,2), 2.84 (m,2), 1.97 (m,2), 1.64 (m,4), 1.26 (t,3,J=7.1).

b. 4-[3-(Ethoxycarbonylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine.Using the procedure of Example 1.j, replacing1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with1-benzyloxycarbonyl-4-[3-(ethoxycarbonylmethyl)-2-oxoperhydropyrimidin-1-yl]piperidine,the piperidine was obtained as a viscous oil; MS: m/z=270(M+1); NMR(CDCl₃): 4.41 (m,1), 4.19 (q,2, J=7.1), 4.07 (s,2), 3.32 (m,2), 3.24(m,2), 3.12 (m,2), 2.70 (m,2), 2.09 (m,1), 1.98 (m,2), 1.63 (m,4), 1.27(t,3, J=7.1).

EXAMPLE 16(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-ethylbenzamidecitrate

Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-(2-oxoperhydropyrimidin-1-yl)piperidine andN-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-benzamide with(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-ethylbenzamide, the titlecompound was obtained as a white solid; MS: m/z=531(M+1); Analysis forC₂₈H₃₆Cl₂N₄O₂.1.10 C₆H₈O₇.0.30 H₂O: Calculated: C, 55.53; H, 6.11; N,7.48; Found: C, 55.51; H, 6.19; N, 7.47.

The intermediate(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-ethylbenzamide was preparedas follows.

a. (S)-N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]benzamide. Benzoicanhydride (14.6 g) in dichloromethane (50 mL) was added dropwise to asolution of (S)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine (15.0 g) andtriethylamine (9.0 mL) in dichloromethane (200 mL) at 0° C. After beingstirred at 0° C. for 1 hour and then at ambient temperature for 1 hour,the reaction mixture was washed (1 N hydrochloric acid, saturatedaqueous sodium bicarbonate), and the separated organic phase was driedand evaporated. The crude product was chromatographed, withdichloromethane/methanol (gradient 98:2, 90:10) as eluent, to give theamide as a light yellow gum (17.5 g); MS: m/z=338(M+1); NMR (CDCl₃):7.65 (m,2), 7.48 (m,1), 7.38 (m,3), 7.33 (d,1, J=2.1), 7.07 (dd,1,J=2.1, 8.2), 6.44 (m,1,NH), 3.83 (m,1), 3.70 (m,1), 3.58-3.41 (m,2),3.13 (m,1), 2.47 (m,1, OH), 1.99 (m,1), 1.84 (m,1).

b. (S)-N-[4-Acetoxy-2-(3,4-dichlorophenyl)butyl]benzamide. Acetylchloride (4.6 mL) was added dropwise to a solution of(S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]benzamide (17.5 g) andpyridine (8.4 mL) in dichloromethane (400 mL) at 0 ° C. After beingstirred overnight at room temperature, the reaction mixture was washed(water, saturated aqueous copper(II) sulfate), and the separated organicphase was dried and evaporated to give the acetyl-compound as a lightyellow oil; MS: m/z=380(M+1); NMR (CDCl₃): 7.63 (m,2), 7.48 (m,1), 7.39(m,3), 7.32 (d,1, J=2.1), 7.06 (dd,1, J=2.1, 8.2), 6.21 (m,1), 4.03(m,1), 3.87 (m,2), 3.41 (m,1), 3.07 (m,1), 2.09 (m,1), 1.98 (s,3), 1.92(m,1).

c. (S)-N-[4-Acetoxy-2-(3,4-dichlorophenyl)butyl]-N-ethylbenzamide.(S)-N-[4-Acetoxy-2-(3,4-dichlorophenyl)butyl]benzamide (4.2 g) intetrahydrofuran (15 mL) was cannulated into a suspension of sodiumhydride (0.58 g, 60% dispersion in mineral oil) and iodoethane (1.0 mL)in tetrahydrofuran (5 mL). After being stirred overnight, the reactionmixture was concentrated in vacuo, dissolved in dichloromethane, andwashed with water. The separated organic layer was dried, evaporated,and chromatographed, with dichloromethane:ether (10:1) as eluent, togive the N-ethyl compound as an oil (3.7 g); MS: m/z=408(M+1).

d. (S)-N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-ethyl-benzamide. Asolution of(S)-N-[4-acetoxy-2-(3,4-dichlorophenyl)butyl]-N-ethylbenzamide (3.7 g)in 1 N sodium hydroxide (27 mL), tetrahydrofuran (70 mL), water (20 mL),and methanol (15 mL) was stirred for 3 hours. The reaction mixture wasconcentrated in vacuo, dissolved in dichloromethane, and washed withwater. The separated organic layer was dried and evaporated to give thealcohol as an oil (3.2 g); MS: m/z=366(M+1).

e. (S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-ethylbenzamide. To asolution of oxalyl chloride (1.3 mL) in dichloromethane (30 mL) at −78°C. was added dimethylsulfoxide (2.1 mL) in dichloromethane (10 mL),followed by(S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-ethylbenzamide (3.2 g)in dichloromethane (15 mL) within 5 minutes. After 15 minutes,triethylamine (8.2 mL) was added, and the reaction mixture was allowedto warm to ambient temperature. The mixture was diluted withdichloromethane, and washed with dilute aqueous hydrochloric acid,water, and aqueous sodium bicarbonate. The separated organic layer wasdried, evaporated, and chromatographed, withdichloromethane:ether:hexane (2:1:1) as eluent, to give the _(t)ldehydeas an oil (2.5 g); MS: m/z=364(M+1).

EXAMPLE 17(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-4-fluoro-N-methylbenzamidecitrate

4-Fluorobenzoyl chloride (0.115 mL) was added to a solution of(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylamine(0.400 g) and pyridine (0.16 mL) in dichloromethane (10 mL) at −30° C.The reaction mixture was allowed to warm to ambient temperature andstirred for 1 hour. The mixture was diluted with dichloromethane, washed(aqueous sodium bicarbonate, saturated aqueous copper(II) sulfate),dried, and evaporated. The crude product was chromatographed, withdichloromethane:methanol (gradient 98:2, 80:10) as eluent. The purifiedproduct (0.350 g) and citric acid (0.126 g) were dissolved in methanoland evaporated to give the title compound as a glass which was scrapedout as a white solid (0.450 g); MS: m/z=535(M+1); Analysis forC₂₇H₃₃Cl₂FN₄O₂.1.10 C₆H₈O₇.0.10 (C₂H₅)₂O.0.70 H₂O: Calculated: C, 53.25;H, 5.80; N, 7.30; Found: C, 53.22; H, 5.70; N, 7.30.

The intermediate(S)-N-12-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl)-N-methylaminewas prepared as follows:

a. tert-Butyl(S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylcarbamate.Di-tert-butyl dicarbonate (21.6 g) in dichloromethane (125 mL) was addeddropwise to a solution of(S)-N-methyl-2-(3,4-dichlorophenyl)-4-hydroxybutylamine (25.0 g) indichloromethane (125 mL) over a period of 30 minutes. After beingstirred for 3 hours, the reaction mixture was washed (0.1 N hydrochloricacid, aqueous sodium bicarbonate), dried, and evaporated. The crudeproduct was chromatographed, with dichloromethane:ether (2:1) as eluent,to give the tert-butyl ester as an oil (33.0 g) that crystallized uponstanding.

b. tert-Butyl(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylcarbamate. Using theprocedure of Example 16. e, replacing(S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-ethylbenzamide withtert-Butyl(S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-carbamate, thealdehyde was obtained as an oil that was used crude in the followingreaction.

c. tert-Butyl(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl3-N-methylcarbamate.Using the procedure of Example 10, replacing4-(3-methyl-2-oxoperhydropyrimidin-1-yl)piperidine with4-(2-oxoperhydropyrimidin-1-yl)piperidine andN-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with tert-Butyl(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylcarbamate, the titlecompound was obtained as a gum.

d.(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylamine.Trifluoroacetic acid (7.5 mL) was added to a solution of tert-butyl(S)-N-[12-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylcarbamate(5.1 g) in dichloromethane (200 mL). After 30 minutes, additionaltrifluoroacetic acid (7.5 mL) was added, and the reaction mixture wasstirred for 4 hours. The mixture was washed with 1 N sodium hydroxide(250 mL), dried, and evaporated to give the title compound as a gum (3.8g); MS: m/z=413(M+1).

EXAMPLE 18(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-4-methyl-N-methylbenzamidecitrate

Using a procedure similar to that described in Example 17, exceptreplacing 4-fluorobenzoyl chloride with p-toluoyl chloride, the titlecompound was obtained as a white solid; MS: m/z=531(M+1); Analysis forC₂₈H₃₆Cl₂N₄O₂.1.10 C₆H₈O₇.0.10 (C₂H₅)₂O.0.30 H₂O: Calculated: C, 55.63;H, 6.18; N, 7.41; Found: C, 55.58; H, 6.17; N, 7.52.

EXAMPLE 19(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-4-methoxy-N-methylbenzamidecitrate

Using the same procedure as Example 17, replacing 4-fluorobenzoylchloride with 4-methoxybenzoyl chloride, the title compound was obtainedas a white solid; MS: m/z=547(M+1); Analysis for C₂₈H₃₆Cl₂N₄O₃.1.10C₆H₈O₇.0.10 (C₂H₅)₂O..0.70 H₂O: Calculated: C, 53.92; H, 6.10; N, 7.19;Found: C, 53.93; H, 5.99; N, 7.19.

EXAMPLE 20(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-4-hydroxy-N-methylbenzamidecitrate

A solution of(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylamine(1.22 g), 4-acetoxybenzoic acid (0.640 g), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.682 g) indichloromethane (30 mL) was stirred overnight. The reaction mixture wasdiluted with dichloromethane, washed (water, aqueous sodiumbicarbonate), dried, and evaporated. The crude product waschromatographed twice, with dichloromethane:methanol (gradient 95:5,80:20) as eluent. The purified product (0.190 g) and citric acid (0.069g) were dissolved in methanol and evaporated to give the title compoundas a glass which was scraped out as a white solid (0.220 g); MS:m/z=533(M+1); Analysis for C₂₇H₃₄Cl₂N₄O₃.1.10 C₆H₈O₇.0.60 H₂O:Calculated: C, 53.40; H, 5.86; N, 7.41; Found: C, 53.45; H, 6.13; N,7.26.

EXAMPLE 211-[(S)-N-Benzoyl-3-(3,4-dichlorophenyl)-N-methyl-4-aminobutyl]-4-(2-oxoperhydropyrimidin-1-yl)piperidine1-oxide

3-Chloroperoxybenzoic acid (0.700 g) in dichloromethane (16 mL) wasadded dropwise to a solution of(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide(1.31 g) in dichloromethane (12 mL) at 0° C. After being stirred for 1hour, the reaction mixture was diluted with dichloromethane, washed withaqueous sodium bicarbonate, dried, and evaporated. The crude product waschromatographed, with dichloromethane:methanol (gradient 98:2, 70:30) aseluent. The purified product (0.592 g) and p-toluenesulfonic acidmonohydrate (0.232 g) were dissolved in dichloromethane:methanol andevaporated to give the title compound as a white solid (0.824 g); MS:m/z=533(M+1); Analysis for C₂₇H ₃₄Cl₂N₄O₃.1.10 C₇H₈O₃S.1.10 H₂O:Calculated: C, 56.11; H, 6.10; N, 7.54; Found: C, 55.85; H, 5.96; N,7.33.

EXAMPLE 22N-[2-(3,4-Dichlorophenyl)-4-[4-(3-methyl-2-oxoimidazolidin-1-yl)piperidino]butyl]-N-methylbenzamidehydrochloride

To a suspension of sodium hydride (30 mg, 60% dispersion in oil) intetrahydrofuran (1 mL) was addedN-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoimidazolidin-1-yl)piperidino]butyl]-N-methylbenzamide(152 mg) in tetrahydrofuron (2 mL). After 30 minutes, iodomethane (0.021mL) was added, and the reaction mixture was stirred for 2.5 hours. Themixture was diluted with dichloromethane and washed with water. Theseparated organic layer was dried and evaporated to an oil, which wasdissolved in a minimum amount of dichloromethane and precipitated outwith ethereal hydrogen chloride. The solvent was evaporated to an offwhite solid (104 mg); MS: m/z=517(M+1); Analysis for C₂₇H₃₄N₄O₂Cl₂.1.2HCl.0.1 (C₂H₅)₂O: Calculated: C, 57.83; H, 6.42; N, 10.05; Found: C,57.85; H, 6.41; N, 9.85.

The intermediateN-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoimidazolidin-1-yl)piperidino]butyl]-N-methylbenzamidewas prepared using a sequence similar to that described in Example 3 andthe sub-parts thereof by substitutingN-[-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide for the(S)-N-[-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide used insub-part 3. d.

2 1 15 DNA ARTIFICIAL SEQUENCE Designed oligonucleotide complementary tosequence 2 and providing an internal Hind III site 1 gcgcaagctt atggg 152 18 DNA ARTIFICIAL SEQUENCE Designed oligonucleotide complementary tosequence 1, providing an internal Hind III site and an Eco 0109compatible end. 2 gtccccataa gcttgcgc 18

What is claimed is:
 1. A process for preparing a compound according toformula I

wherein: m is 2 or 3; D is a residue of formula Ia or formula Ib

Q is phenyl which may have one or two substituents independentlyselected from halo, trifluoromethyl, hydroxy, (C₁₋₃)alkoxy, (C₁₋₃)alkyland methylenedioxy; or Q is thienyl, imidazolyl, benzo[b]thiophenyl ornaphthyl any of which may have a halo substituent; or Q is biphenylyl;or Q is carbon-linked indolyl which may have a benzyl substituent at the1-position; Q^(a) is hydrogen, (C₁₋₄)alkyl, or a radical of formula—(CH₂)_(q)—NR⁵R⁶ in which q is 2 or 3 and R⁵ and R⁶ are independently(C₁₋₄)alkyl or NR⁵R⁶ is piperidino or 4-benzylpiperidino; R¹ ishydrogen, methyl or (C₂₋₆)n-alkyl which may have a terminal aminoradical; R² is —C(═O)R³, —C(═O)OR³ or —C(═J¹)NHR³ in which J¹ is oxygenor sulfur and R³ is hydrogen, (C₁₋₆)alkyl, phenyl(C₁₋₃)alkyl (whichphenyl may have one or more substituents selected from halo, hydroxy,(C₁₋₄)alkoxy or (C₁₋₄)alkyl), pyridyl(C₁₋₃)alkyl, naphthyl(C₁₋₃)alkyl,pyridylthio(C₁₋₃)alkyl, styryl, 1-methylimidazol-2-ylthio(C₁₋₃)alkyl,aryl (which may have one or more substituents selected from halo,hydroxy, (C₁₋₄)alkoxy or (C₁₋₄)alkyl), heteroaryl (which may have one ormore halo, hydroxy, (C₁₋₄)alkoxy or (C₁₋₄)alkyl substituents), or R³ maybe α-hydroxybenzyl when R² is —COR³; n is 0, 1, 2 or 3; J² is oxygen ortwo hydrogens; p is 1 or 2, and when p is 2, n is 1 and J² is twohydrogens; L⁶ is carbonyl or methylene; r is 0, 1, 2 , or 3; R⁴ isphenyl which may have one or more substituents selected from halo,trifluoromethyl, (C₁₋₄)alkyl, hydroxy or (C₁₋₄)alkoxy; naphthyl whichmay have one or more substituents selected from halo, trifluoromethyl,(C₁₋₄)alkyl or hydroxy; pyridyl; thienyl; indolyl; quinolinyl;benzothienyl or imidazolyl; or when L⁶ is carbonyl, the group—(CH₂)_(r)—R⁴ may be aryl, heteroaryl or a benzyl group having anα-substituent selected from hydroxy, (C₁₋₄)alkoxy and (C₁₋₄)alkyl, andfurther wherein the aryl, heteroaryl or phenyl portion of the benzylgroup may have one or more substituents selected independently fromhalo, trifluoromethyl, (C₁₋₄)alkyl, hydroxy and (C₁₋₄)alkyl, hydroxy and(C₁₋₄)alkoxy; G denotes a single bond, a double bond or a divalenthydrocarbon radical; J denotes a radical joined to the ring by a singlebond if G denotes a double bond or, otherwise, a radical joined by adouble bond; M denotes a heteroatom or substituted heteroatom; and Ldenotes a hydrocarbon radical in which the 1-position is attached to M;wherein the values of G, J, M and L in combination are selected from (a)G is a single bond; J is oxo or thioxo; M is oxy, thio or NR¹²; and L isL¹; (b) G is a single bond; J is NR⁸; M is NR⁷; and L is L¹; (c) G is adouble bond, J is OR⁷, SR⁷ or NR⁹R¹⁰; M is nitrogen; and L is L¹; (d) Gis methylene which may have one or two methyl substituents; J is oxo,thio or NR¹¹; M is oxy, thio, sulfinyl, sulfonyl or NR⁷; and L is L²;(e) G is a single bond; J is oxo, thioxo or NR¹¹; M is nitrogen; and Lis L³; (f) G is methine, which may have a (1-3C)alkyl substituent; J isoxo, thioxo or NR¹¹; M is nitrogen; and L is L⁴; and (g) G iscis-vinylene, which may have one or two methyl substituents; J is oxo,thioxo, or NR¹¹; M is nitrogen; and L is L⁵; wherein R⁷ is hydrogen or(C₁₋₃)alkyl; R⁸ is hydrogen, (C₁₋₃)alkyl, cyano, (C₁₋₃)alkylsulfonyl ornitro; R⁹ and R¹⁰ are independently hydrogen or (C₁₋₃)alkyl or theradical NR⁹R¹⁰ is pyrrolidino, piperidino, morpholino, thiomorpholino orits S-oxide, or piperazino which may have a (C₁₋₃)alkyl substituent atthe 4-position; R¹¹ is hydrogen or (C₁₋₃)alkyl; R¹² is hydrogen,(C₁₋₃)alkyl, RaOC(═O)CH₂— or RbRcNC(═O)CH₂—, where Ra is hydrogen or(C₁₋₃)alkyl, and Rb and Rc are independently hydrogen, (C₁₋₃)alkyl,phenyl or benzyl; L¹ is ethylene, cis-vinylene, trimethylene ortetramethylene which radical L¹ itself may have one or two methylsubstituents; L² is ethylene or trimethylene which radical L² itself mayhave one or two methyl substituents; L³ is prop-2-en-1-yliden-3-yl,which radical L³ itself may have one or two methyl substituents; L⁴ iscis-vinylene, which radical L⁴ itself may have one or two methylsubstituents; and L⁵ is methine, which radical L⁵ itself may have a(C₁₋₃)alkyl substituent; and compounds wherein the nitrogen identifiedby Δ is an N-oxide or a quadricovalent ammonium nitrogen where thefourth radical on the nitrogen is (C₁₋₄)alkyl or benzyl and theassociated counterion is a pharmaceutically acceptable anion, or apharmaceutically acceptable salt of said compound of formula I or saidN-oxide, said process comprising a) reductively alkylating4-oxopiperidine under mild acid conditions with an aldehyde of formulaIV

 followed by reduction with sodium cyanoborohydride in an alcoholicsolvent, or, alkylating said piperidine with an alkylating agent offormula V

wherein Y is a leaving up selected from iodide, bromide,methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, to forma piperidone of formula VII

b) reductively alkylating said piperidone of formula VII with an amineof formula HML-NH₂ to form an amine of formula III

c) cyclizing said amine by reacting it with a diactivated carbonic acidderivative selected from 1,1′-carbonyldiimidazole, chloroformate estersselected from methyl, ethyl or phenyl esters, and carbonate diestersselected from phosgene, diphosgene and triphosgene; or with adiactivated thiocarbonyl derivative selected from1,1′-thiocarbonyldi-2(1H)-pyridone, 1,1′-thiocarbonyldiimidazole, phenylchlorodithioformate and thiophosgene; said cyclization being carried inan inert solvent, selected from chloroform, tetrahydrofuran or toluene,at a temperature from about ambient temperature to the refluxtemperature of the reaction mixture to form a compound of said formulaI.
 2. The process of claim 1, wherein in said compound according toformula I, R⁴ is phenyl which may have one or more substituents selectedfrom chloro or fluoro; or, when L⁶ is carbonyl, the group —(CH₂)_(r)—R⁴may be aryl, heteroaryl or a benzyl group having an α-substituentselected from hydroxy, (C₁₋₄)alkoxy and (C₁₋₄)alkyl, and further whereinthe aryl, heteroaryl or phenyl portion of the benzyl group may have oneor more substituents selected independently from chloro or fluoro. 3.The process according to claim 1, for preparing a compound according toformula I

wherein: G is a single bond; J is oxo; M is NR¹²; L is L¹, and R¹², Dand m are as defined in claim 3, and wherein said step b) comprises:cyclizing said amine by reacting it with a diactivated carbonic acidderivative selected from 1,1′-carbonyldiimidazole, chloroformate estersselected from methyl, ethyl or phenyl esters, and carbonate diestersselected from phosgene, diphosgene and triphosgene.
 4. The processaccording to claim 3, wherein said step b) comprises cyclizing saidamine by reacting it with 1,1′-carbonyldiimidazole.
 5. The processaccording to claim 1, for preparing a compound according to formula I

wherein: G is a single bond; J is thioxo; M is NR¹²; L is L¹, and R¹², Dand m are as defined in claim 3, and wherein said step b) comprises:cyclizing said amine by reacting it with a diactivated thiocarbonylderivative selected from 1,1′-thiocarbonyldi-2(1H)-pyridone,1,1′-thiocarbonyldiimidazole, phenyl chlorodithioformate andthiophosgene.
 6. The process according to claim 5, wherein said step b)comprises cyclizing said amine by reacting it with1′-thiocarbonyldiimidazole.
 7. A process for preparing a compoundaccording to formula I

wherein: m is 2 or 3; D is a residue of Ia or formula Ib

Q is phenyl which may have one or two substituents independentlyselected from halo, trifluoromethyl, hydroxy, (C₁₋₃)alkoxy, (C₁₋₃)alkyland methylenedioxy; or Q is thienyl, imidazolyl, benzo[b]thiophenyl ornaphthyl any of which may have a halo substituent; or Q is biphenylyl;or Q is carbon-linked indolyl which may have a benzyl substituent at the1-position; Q^(a) is hydrogen, (C₁₋₄)alkyl, or a radical of formula—(CH₂)_(q)—NR⁵R⁶ in which q is 2 or 3 and R⁵ and R⁶ are independently(C₁₋₄)alkyl or NR⁵R⁶ is piperidino or 4-benzylpiperidino; R¹ ishydrogen, methyl or (C₂₋₆)n-alkyl which may have a terminal aminoradical; R² is —C(═O)R³, —C(═O)OR³ or —C(═J¹)NHR³ in which J¹ is oxygenor sulfur and R³ is hydrogen, (C₁₋₆)alkyl, phenyl(C₁₋₃)alkyl (whichphenyl may have one or more substituents selected from halo, hydroxy,(C₁₋₄)alkoxy or (C₁₋₄)alkyl), pyridyl(C₁₋₃)alkyl, naphthyl(C₁₋₃)alkyl,pyridylthio(C₁₋₃)alkyl, styryl, 1-methylimidazol-2-ylthio(C₁₋₃)alkyl,aryl (which may have one or more substituents selected from halo,hydroxy, (C₁₋₄)alkoxy or (C₁₋₄)alkyl), heteroaryl (which may have one ormore halo, hydroxy, (C₁₋₄)alkoxy or (C₁₋₄)alkyl substituents), or R³ maybe α-hydroxybenzyl when R² is —COR³; n is 0, 1, 2 or 3; j²is oxygen ortwo hydrogens; p is 1 or 2, and when p is 2, n is 1 and J² is twohydrogens; L⁶ is carbonyl or methylene; r is 0, 1, 2, or 3; R⁴ is phenylwhich may have one or more substituents selected from halo,trifluoromethyl, (C₁₋₄)alkyl, hydroxy or (C₁₋₄)alkoxy; naphthyl whichmay have one or more substituents selected from halo, trifluoromethyl,(C₁₋₄)alkyl or hydroxy; pyridyl; thienyl; indolyl; quinolinyl;benzothienyl or imidazolyl; or when L⁶ is carbonyl, the group—(CH₂)_(r)—R⁴ may be aryl, heteroaryl or a benzyl group having anα-substituent selected from hydroxy, (C₁₋₄)alkoxy and (C₁₋₄)alkyl, andfurther wherein the aryl, heteroaryl or phenyl portion of the benzylgroup may have one or more substituents selected independently fromhalo, trifluoromethyl, (C₁₋₄)alkyl, hydroxy and (C₁₋₄)alkyl, hydroxy and(C₁₋₄)alkoxy; G denotes a single bond, a double bond or a divalenthydrocarbon radical; J denotes a radical joined to the ring by a singlebond if G denotes a double bond or, otherwise, a radical joined by adouble bond; M denotes a heteroatom or substituted heteroatom; and Ldenotes a hydrocarbon radical in which the 1-position is attached to M;wherein the values of G, J, M and L in combination are selected from (a)G is a single bond; J is oxo or thioxo; M is oxy, thio or NR¹²; and L isL¹; (b) G is a single bond; J is NR⁸; M is NR⁷; and L is L¹; (c) G is adouble bond, J is OR⁷, SR⁷ or NR⁹R¹⁰; M is nitrogen; and L is L¹; (d) Gis methylene which may have one or two methyl substituents; J is oxo,thio or NR¹¹; M is oxy, thio, sulfinyl, sulfonyl or NR⁷; and L is L²;(e) G is a single bond; J is oxo, thioxo or NR¹¹; M is nitrogen; and Lis L³; (f) G is methine, which may have a (1-3C)alkyl substituent; J isoxo, thioxo or NR¹¹; M is nitrogen; and L is L⁴; and (g) G iscis-vinylene, which may have one or two methyl substituents; J is oxo,thioxo, or NR¹¹; M is nitrogen; and L is L⁵; wherein R⁷ is hydrogen or(C₁₋₃)alkyl; R⁸ is hydrogen, (C₁₋₃)alkyl, cyano, (C₁₋₃)alkylsulfonyl ornitro; R⁹ and R¹⁰ are independently hydrogen or (C₁₋₃)alkyl or theradical NR⁹R¹⁰ is pyrrolidino, piperidino, morpholino, thiomorpholino orits S-oxide, or piperazino which may have a (C₁₋₃)alkyl substituent atthe 4-position; R¹¹ is hydrogen or (C₁₋₃)alkyl; R¹² is hydrogen,(C₁₋₃)alkyl, RaOC(═O)CH₂— or RbRcNC(═O)CH₂—, where Ra is hydrogen or(C₁₋₃)alkyl, and Rb and Rc are independently hydrogen, (C₁₋₃)alkyl,phenyl or benzyl; L¹ is ethylene, cis-vinylene, trimethylene ortetramethylene which radical L¹ itself may have one or two methylsubstituents; L² is ethylene or trimethylene which radical L² itself mayhave one or two methyl substituents; L³ is prop-2-en-1-yliden-3-yl,which radical L³ itself may have one or two methyl substituents; L⁴ iscis-vinylene, which radical L⁴ itself may have one or two methylsubstituents; and L⁵ is methine, which radical L⁵ itself may have a(C₁₋₃)alkyl substituent; and compounds wherein the nitrogen identifiedby Δ is an N-oxide or a quadricovalent ammonium nitrogen where thefourth radical on the nitrogen is (C₁₋₄)alkyl or benzyl and theassociated counterion is a pharmaceutically acceptable anion, or apharmaceutically acceptable salt of said compound of formula I or saidN-oxide, said process comprising: a) reacting a protected4-oxopiperidine of the following formula

 wherein Pr is a protecting group such as benzyloxycarbonyl, with anamine of formula HM-L-NH₂ to form an amine of the formula III

b) cyclizing said amine by reacting it with a diactivated carbonic acidderivative selected from 1,1′-carbonyldiimidazole, chloroformate estersselected from methyl, ethyl or phenyl esters, and carbonate diestersselected from phosgene, diphosgene and triphosgene; or with adiactivated thiocarbonyl derivative selected from1,1′-thiocarbonyldi-2(1H)pyridone, 1,1′-thiocarbonyldiimidazole, phenylchlorodithioformate and thiophosgene; said cyclization being carried inan inert solvent, selected from chloroform, tetrahydrofuran or toluene,at a temperature from about ambient temperature to the refluxtemperature of the reaction mixture to form a compound having thefollowing formula

 and deprotecting said compound to form a piperidine of formula II,

c) reductively alkylating said piperidine of formula II under mild acidconditions with an aldehyde of formula IV

 followed by reduction with sodium cyanoborohydride in an alcoholicsolvent, or, alkylating said piperidine of formula II with an alkylatingagent of formula V

wherein Y is a leaving group selected from iodide, bromide,methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate to formsaid compound of formula I.
 8. The process of claim 7, wherein in saidcompound according to formula I, R⁴ is phenyl which may have one or moresubstituents selected from chloro or fluoro; or, when L⁶ is carbonyl,the group —(CH₂)_(r)—R⁴ may be aryl, heteroaryl or a benzyl group havingan α-substituent selected from hydroxy, (C₁₋₄)alkoxy and (C₁₋₄)alkyl,and further wherein the aryl, heteroaryl or phenyl portion of the benzylgroup may have one or more substituents selected independently fromchloro or fluoro.
 9. The process of claim 7, for preparing a compoundaccording to formula I

wherein: G is a single bond; J is oxo; M is NR¹²; L is L¹, and R¹², Dand m are as defined in claim 3, and wherein said step b) comprises:cyclizing said amine by reacting it with a diactivated carbonic acidderivative selected from 1,1′-carbonyldiimidazole, chloroformate estersselected from methyl, ethyl or phenyl esters, and carbonate diestersselected from phosgene, diphosgene and triphosgene.
 10. The processaccording to claim 9, wherein said step b) comprises cyclizing saidamine by reacting it with 1,1′-carbonyldiimidazole.
 11. The processaccording to claim 7, for preparing a compound according to formula I

wherein: G is a single bond; J is thioxo; M is NR¹²; L is L¹, and R¹², Dand m are as defined in claim 3, and wherein said step b) comprises:cyclizing said amine by reacting it with a diactivated thiocarbonylderivative selected from 1,1 ′-thiocarbonyldi-2(1H)-pyridone,1,1′-thiocarbonyldiimidazole, phenyl chlorodithioformate andthiophosgene.
 12. The process according to claim 11, wherein said stepb) comprises cyclizing said amine by reacting it with1,1′-thiocarbonyldiimidazole.